Small molecule inhibitors of ubiquitin specific protease 1 (USP1) and uses thereof

ABSTRACT

The disclosure provides for small molecules inhibitory compounds of ubiquitin specific protease 1 (USP1) and compositions comprising the same. The disclosure further provides methods for targeting ubiquitin specific protease 1 (USP1) and methods of treating diseases or disorders related to USP1, such as cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation application of InternationalApplication No. PCT/CN2022/131293, filed Nov. 11, 2022, which claims thebenefit of International Application No. PCT/CN2021/130290, filed Nov.12, 2021 and International Application No. PCT/CN2022/123827, filed Oct.8, 2022, each of which is incorporated herein by reference in itsentirety.

BACKGROUND

Ubiquitin specific protease 1 (USP1) is a gene that plays a role in aDNA damage repair. Compounds and pharmaceutical compositions targetingUSP1, and methods of treatment for USP1-related diseases and disorders,like certain cancers, have not been widely developed. Therefore, thereremains a need to address methods of treating USP1-related diseases.

SUMMARY

The present disclosure addresses the above need and provides additionaladvantages as well.

In one aspect, described herein is a compound having the structure ofFormula (IVa), or a salt or solvate thereof,

wherein,

-   Y¹ is N or CR^(Y1);-   Y² is N or CR^(Y2);-   Y³ is N or CR^(Y3);-   Y⁴ is N or CR^(Y4);-   R¹ is hydrogen, —CN, optionally substituted C₁₋₆ alkyl, optionally    substituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl,    optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₈    cycloalkyl, or optionally substituted C₂₋₇ heterocycloalkyl;-   each of R⁴ and R^(4′) is independently selected from hydrogen, halo,    —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl,    optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆    alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionally    substituted C₂₋₇ heterocycloalkyl; or R⁴ and R^(4′) taken together    form an oxo; or R⁴ and R^(4′) taken together with the carbon to    which they are attached form a 3-6 membered cycloalkyl or 3-6    membered heterocycloalkyl;-   each of R⁵ and R^(5′) is independently selected from hydrogen, halo,    —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl,    optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆    alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionally    substituted C₂₋₇ heterocycloalkyl; or R⁵ and R^(5′) taken together    form an oxo; or R⁵ and R^(5′) taken together with the carbon to    which they are attached form a 3-6 membered cycloalkyl or 3-6    membered heterocycloalkyl;-   each of R⁶ and R^(6′) is independently selected from hydrogen, halo,    —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl,    optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆    alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionally    substituted C₂₋₇ heterocycloalkyl; or R⁶ and R^(6′) taken together    form an oxo; or R⁶ and R^(6′) taken together with the carbon to    which they are attached form a 3-6 membered cycloalkyl or 3-6    membered heterocycloalkyl;-   each of R⁸ and R⁹ is independently selected from hydrogen, halo,    —CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆    heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionally    substituted C₂₋₆ alkynyl; or R⁸ and R⁹ taken together with the    carbon to which they are attached form an optionally substituted 3-6    membered cycloalkyl or 3-6 membered heterocycloalkyl;-   ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic    heterocycloalkyl, or bicyclic heterocycloalkyl;-   each of R^(A) is independently selected from halogen, —NO₂, oxo,    —CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆    alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted    C₁₋₆ heteroalkyl, optionally substituted C₃₋₈ cycloalkyl, optionally    substituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹),    —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),    —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),    —N(R¹²)₂S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹);-   R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally    substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,    optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈    cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, optionally    substituted phenyl, optionally substituted heteroaryl, optionally    substituted —C₁₋₄ alkylene-C₃₋₈ cycloalkyl, optionally substituted    —C₁₋₄ alkylene-C₂₋₇ heterocycloalkyl, optionally substituted —C₁₋₄    alkylene-phenyl, or optionally substituted —C₁₋₄    alkylene-heteroaryl;-   each of R¹² is independently selected from hydrogen, —NO₂, —CN, C₁₋₆    alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆    heteroalkyl, C₃₋₈ carbocycle, and 3- to 6-membered heterocycle,    wherein the C₃₋₆ carbocycle and 3- to 6-membered heterocycle is    optionally substituted with one or more substituents independently    selected from halogen, —OH, oxo, amino, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆    alkoxy, and C₁₋₆ haloalkyl;-   R^(B1) is optionally substituted C₃₋₈ cycloalkyl, optionally    substituted C₂₋₉ heterocycloalkyl, optionally substituted naphthyl,    optionally substituted phenyl, optionally substituted monocyclic    heteroaryl, or optionally substituted bicyclic heteroaryl;-   each of R^(Y1), R^(Y2), R^(Y3) and R^(Y4) is independently selected    from hydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹),    optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆    heteroalkyl, optionally substituted C₂₋₆ alkenyl, optionally    substituted C₂₋₆ alkynyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,    —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),    —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),    —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², —S(O)₂N(R¹²)(R¹¹),    optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₂₋₉    heterocycloalkyl, optionally substituted naphthyl, optionally    substituted phenyl, optionally substituted monocyclic heteroaryl,    and optionally substituted bicyclic heteroaryl; or-   R^(Y1) and R^(Y2) are taken together with the carbons to which they    are attached to form an optionally substituted C₃₋₈ cycloalkyl or    optionally substituted C₂₋₉ heterocycloalkyl; or-   R^(Y3) and R^(Y4) are taken together with the carbons to which they    are attached to form an optionally substituted C₃₋₈ cycloalkyl or    optionally substituted C₂₋₉ heterocycloalkyl;-   m is 0, 1, 2, 3, or 4; and-   p is 0 or 1.

In some embodiments, the compound has a structure of Formula (IVa-1),

In some embodiments, the compound has a structure of Formula (IVa-2),

In one aspect, described herein is a compound having the structure ofFormula (VI), or a salt or solvate thereof,

wherein,

-   ring C is an optionally substituted 5 membered heteroaryl;-   ring D is an aromatic, saturated or partially saturated 6 membered    carbocycle or heterocycle, wherein each of the carbocycle or    heterocycle is optionally substituted;-   each of R⁸ and R⁹ is independently selected from hydrogen, halo,    —CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆    heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionally    substituted C₂₋₆ alkynyl; or R⁸ and R⁹ taken together form an oxo;    or R⁸ and R⁹ taken together with the carbon to which they are    attached form an optionally substituted 3-6 membered cycloalkyl or    heterocycloalkyl;-   ring A is phenyl, naphthyl, monocyclic heteroaryl, bicyclic    heteroaryl, cycloalkyl or heterocycloalkyl;-   each of R^(A) is independently selected from halogen, —NO₂, oxo,    —CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆    alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted    C₁₋₆ heteroalkyl, optionally substituted C₃₋₈ cycloalkyl, optionally    substituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹),    —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),    —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),    —N(R¹²)₂S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹);-   R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally    substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,    optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈    cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, optionally    substituted phenyl, optionally substituted heteroaryl, optionally    substituted —C₁₋₄ alkylene-C₃₋₈ cycloalkyl, optionally substituted    —C₁₋₄ alkylene-C₂₋₇ heterocycloalkyl, optionally substituted —C₁₋₄    alkylene-phenyl, or optionally substituted —C₁₋₄    alkylene-heteroaryl;-   each of R¹² is independently selected from hydrogen, —NO₂, —CN, C₁₋₆    alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, and C₃₋₆    carbocycle, 3- to 6-membered heterocycle, wherein the C₃₋₆    carbocycle and 3- to 6-membered heterocycle is optionally    substituted with one or more substituents independently selected    from halogen, —OH, oxo, amino, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy,    and C₁₋₆ haloalkyl;-   R^(B) is hydrogen, halo, —CN, —NO₂, optionally substituted C₁₋₆    alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted    C₂₋₆ alkynyl, optionally substituted C₁₋₆ heteroalkyl, —OR¹¹, —SR¹¹,    —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹),    —C(O)N(R²)(R¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,    —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹²,    —S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl,    optionally substituted C₂₋₉ heterocycloalkyl, optionally substituted    naphthyl, optionally substituted phenyl, optionally substituted    monocyclic heteroaryl, or optionally substituted bicyclic    heteroaryl;-   m is 1, 2, 3, or 4; and-   p is 0 or 1.

In one aspect, described herein is a pharmaceutical compositioncomprising a compound described herein or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier orexcipient.

In one aspect, described herein is a method of modulating ubiquitinspecific protease 1 (USP1) in a subject, the method comprisingadministering to a subject a compound described herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition of a compound described herein.

In one aspect, described herein is a method of inhibiting ubiquitinspecific protease 1 (USP1) in a subject, the method comprisingadministering to the subject a compound described herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition of a compound described herein.

In one aspect, described herein is a method of inhibiting or reducingDNA repair activity modulated by ubiquitin specific protease 1 (USP1) ina subject, the method comprising administering to the subject in needthereof an effective amount of a compound described herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition of a compound described herein.

In one aspect, described herein is a method of treating a disease ordisorder associated with ubiquitin specific protease 1 (USP1) in asubject, the method comprising administering to the subject a compounddescribed herein, or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition of a compound described herein.

In one aspect, described herein is a method of treating a disease ordisorder associated with modulation of ubiquitin specific protease 1(USP1) in a subject, the method comprising administering to the subjecta compound described herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition of a compound describedherein. In some embodiments, the disease or disorder is cancer.

In one aspect, described herein is a method of treating cancer in asubject, the method comprising administering to the subject in needthereof an effective amount of a compound described herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition of a compound described herein. In some embodiments, thecancer is selected from the group consisting of lung cancer, non-smallcell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma,ovarian cancer, skin cancer, and breast cancer. In some embodiments, thecancer is ovarian cancer. In some embodiments, the cancer is a breastcancer. In some embodiments, the cancer is a ovarian cancer or breastcancer.

In some embodiments, the cancer comprises cancer cells with elevatedlevels of RAD 18. In some embodiments, the cancer is a DNA damage repairpathway deficient cancer. In some embodiments, the cancer is a PARPinhibitor resistant or refractory cancer. In some embodiments, thecancer is a BRCA1 mutant cancer and/or a BRCA2 mutant cancer. In someembodiments, the cancer is a BRAC1-deficient cancer.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent publications and patents or patent applicationsincorporated by reference contradict the disclosure contained in thespecification, the specification is intended to supersede and/or takeprecedence over any such contradictory material.

DETAILED DESCRIPTION

While various embodiments of the disclosure have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions can occur to those skilled in theart without departing from the disclosure. It should be understood thatvarious alternatives to the embodiments of the disclosure describedherein can be employed.

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this disclosure belongs. All patents and publicationsreferred to herein are incorporated by reference.

“Alkyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbonmono-radical, and preferably having from one to fifteen carbon atoms(i.e., C₁-C₁₅ alkyl). In certain embodiments, an alkyl comprises one tothirteen carbon atoms (i.e., C₁-C₁₃ alkyl). In certain embodiments, analkyl comprises one to eight carbon atoms (i.e., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (i.e., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (i.e., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (i.e., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (i.e., C₁-C₂ alkyl). Whenever itappears herein, a numerical range such as “C₁-C₃ alkyl” means that thealkyl group consists of 1 carbon atom, 2 carbon atoms, or 3 carbonatoms. In other embodiments, an alkyl comprises one carbon atom (i.e.,C₁ alkyl). In other embodiments, an alkyl comprises five to fifteencarbon atoms (i.e., C₅-C₁₅ alkyl). In other embodiments, an alkylcomprises five to eight carbon atoms (i.e., C₅-C₈ alkyl). In otherembodiments, an alkyl comprises two to five carbon atoms (i.e., C₂-C₅alkyl). In other embodiments, an alkyl comprises three to five carbonatoms (i.e., C₃-C₅ alkyl). In certain embodiments, the alkyl group isselected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl(n-pentyl). In other embodiments, examples include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups,such as heptyl, octyl, and the like. The alkyl is attached to the restof the molecule by a single bond. Unless stated otherwise specificallyin the specification, an alkyl group is optionally substituted, forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, the alkyl is optionally substituted with oxo, halogen,—CN, —CF₃, —OH, —OMe, —NH₂, —NO₂, or —C≡CH. In some embodiments, thealkyl is optionally substituted with oxo, halogen, —CN, —CF₃, —OH, or—OMe. In some embodiments, the alkyl is optionally substituted withhalogen such as F.

As used herein, C₁-C_(x)(or C_(1-x)) includes C₁-C₂, C₁-C₃ . . .C₁-C_(x). By way of example only, a group designated as “C₁-C₄”indicates that there are one to four carbon atoms in the moiety, i.e.groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4carbon atoms. Thus, by way of example only, “C₁-C₄ alkyl” indicates thatthere are one to four carbon atoms in the alkyl group, i.e., the alkylgroup is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, and t-butyl. Also, by way of example, C₀-C₂alkylene includes a direct bond, —CH₂—, and —CH₂CH₂— linkages.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above. Unlessstated otherwise specifically in the specification, an alkoxy group canbe optionally substituted, for example, with oxo, halogen, amino,nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, analkoxy is optionally substituted with oxo, halogen, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, an alkoxy is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. In someembodiments, the alkoxy is optionally substituted with halogen.

“Alkenyl” refers to an optionally substituted straight or branchedhydrocarbon chain radical group containing at least one carbon-carbondouble bond, and preferably having from two to twelve carbon atoms(i.e., C₂-C₁₂ alkenyl). In certain embodiments, an alkenyl comprises twoto eight carbon atoms (i.e., C₂-C₈ alkenyl). In certain embodiments, analkenyl comprises two to six carbon atoms (i.e., C₂-C₆ alkenyl). Inother embodiments, an alkenyl comprises two to four carbon atoms (i.e.,C₂-C₄ alkenyl). The group can be in either the cis or transconfiguration about the double bond(s), and should be understood toinclude both isomers. Examples include, but are not limited to, ethenyl(—CH═CH₂), 1-propenyl (—CH₂CH═CH₂), isopropenyl [—C(CH₃)═CH₂], butenyl,1,3-butadienyl, and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkenyl” means that the alkenyl group can consistof 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6carbon atoms. Unless stated otherwise specifically in the specification,an alkenyl group is optionally substituted, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, an alkenyl is optionally substituted with oxo, halogen,—CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, an alkenyl isoptionally substituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. Insome embodiments, the alkenyl is optionally substituted with halogen.The alkenyl is attached to the rest of the molecule by a single bond,for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl),but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless statedotherwise specifically in the specification, an alkenyl group isoptionally substituted, for example, with oxo, halogen, amino, nitrile,nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, an alkenyl is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. Insome embodiments, an alkenyl is optionally substituted with oxo,halogen, —CN, —CF₃, —OH, or —OMe. In some embodiments, the alkenyl isoptionally substituted with halogen.

“Alkynyl” refers to an optionally substituted straight or branchedhydrocarbon chain radical group containing at least one carbon-carbontriple bond, and preferably having from two to twelve carbon atoms(i.e., C₂-C₂ alkynyl). In certain embodiments, an alkynyl comprises twoto eight carbon atoms (i.e., C₂-C₈ alkynyl). In other embodiments, analkynyl comprises two to six carbon atoms (i.e., C₂-C₆ alkynyl). Inother embodiments, an alkynyl comprises two to four carbon atoms (i.e.,C₂-C₄ alkynyl). Whenever it appears herein, a numerical range such as“C₂-C₆ alkynyl” means that the alkynyl group can consist of 2 carbonatoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbonatoms. The alkynyl is attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Unless statedotherwise specifically in the specification, an alkynyl group isoptionally substituted, for example, with oxo, halogen, amino, nitrile,nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, an alkynyl is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. Insome embodiments, an alkynyl is optionally substituted with oxo,halogen, —CN, —CF₃, —OH, or —OMe. In some embodiments, the alkynyl isoptionally substituted with halogen.

“Alkylene” or “alkylene chain” refers to an optionally substitutedstraight or branched divalent hydrocarbon chain linking the rest of themolecule to a radical group containing no unsaturation, and preferablyhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through any two carbons within the chain. In certain embodiments, analkylene comprises one to ten carbon atoms (i.e., C₁-C₈ alkylene). Incertain embodiments, an alkylene comprises one to eight carbon atoms(i.e., C₁-C₈ alkylene). In other embodiments, an alkylene comprises oneto five carbon atoms (i.e., C₁-C₅ alkylene). In other embodiments, analkylene comprises one to four carbon atoms (i.e., C₁-C₄ alkylene). Inother embodiments, an alkylene comprises one to three carbon atoms(i.e., C₁-C₃ alkylene). In other embodiments, an alkylene comprises oneto two carbon atoms (i.e., C₁-C₂ alkylene). In other embodiments, analkylene comprises one carbon atom (i.e., C₁ alkylene). In otherembodiments, an alkylene comprises five to eight carbon atoms (i.e.,C₅-C₈ alkylene). In other embodiments, an alkylene comprises two to fivecarbon atoms (i.e., C₂-C₅ alkylene). In other embodiments, an alkylenecomprises three to five carbon atoms (i.e., C₃-C₅ alkylene). Unlessstated otherwise specifically in the specification, an alkylene groupcan be optionally substituted, for example, with oxo, halogen, amino,nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, analkylene is optionally substituted with oxo, halogen, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, an alkylene is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. In someembodiments, the alkylene is optionally substituted with halogen. Insome embodiments, the alkylene is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. Insome embodiments, the alkylene is —CH₂—. In some embodiments, thealkylene is —CH₂CH₂—. In some embodiments, the alkylene is —CH₂CH₂CH₂—.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising at least one aromatic ring. In some embodiments, an arylcomprises hydrogens and 6 to 30 carbon atoms. The aryl radical can be amonocyclic, bicyclic, tricyclic, or tetracyclic ring system, which caninclude fused (when fused with a cycloalkyl or heterocycloalkyl ring,the aryl is bonded through an aromatic ring atom) or bridged ringsystems. In some embodiments, the aryl is a 6- to 10-membered aryl. Insome embodiments, the aryl is a 6-membered aryl. Aryl radicals include,but are not limited to, aryl radicals derived from the hydrocarbon ringsystems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene,benzene, chrysene, fluoranthene, fluorene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In someembodiments, the aryl is phenyl. Unless stated otherwise specifically inthe specification, an aryl can be optionally substituted, for example,with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl,alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, —S(O)₂NH—C₁-C₆alkyl, and thelike. In some embodiments, an aryl is optionally substituted withhalogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, —NO₂, —S(O)₂NH₂,—S(O)₂NHCH₃, —S(O)₂NHCH₂CH₃, —S(O)₂NHCH(CH₃)₂, —S(O)₂N(CH₃)₂, or—S(O)₂NHC(CH₃)₃. In some embodiments, an aryl is optionally substitutedwith halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In someembodiments, the aryl is optionally substituted with halogen. In someembodiments, the aryl is substituted with alkyl, alkenyl, alkynyl,haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl is independently unsubstituted, or substitutedwith halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. “Aralkynyl” refers to a radicalof the formula —R^(e)-aryl, where R^(c) is an alkynylene chain asdefined above.

“Carbocycle” refers to a saturated, unsaturated or aromatic rings inwhich each atom of the ring is carbon. Carbocycle can include 3- to10-membered monocyclic rings and 6- to 12-membered bicyclic rings (suchas spiro, fused, or bridged rings). Each ring of a bicyclic carbocyclecan be selected from saturated, unsaturated, and aromatic rings. Anaromatic ring, e.g., phenyl, can be fused to a saturated or unsaturatedring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combinationof saturated, unsaturated and aromatic bicyclic rings, as valencepermits, are included in the definition of carbocyclic. In an exemplaryembodiment, an aromatic ring, e.g., phenyl, can be fused to a saturatedor unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Abicyclic carbocycle includes any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits. A bicyclic carbocycleincludes any combination of ring sizes such as 4-5 fused ring systems,5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems,5-7 fused ring systems, 6-5 fused ring systems, 6-7 fused ring systems,5-8 fused ring systems, and 6-8 fused ring systems. Exemplarycarbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl,phenyl, indanyl, and naphthyl. The term “unsaturated carbocycle” refersto carbocycles with at least one degree of unsaturation and excludingaromatic carbocycles. Examples of unsaturated carbocycles includecyclohexadiene, cyclohexene, and cyclopentene. The term “saturatedcycloalkyl” as used herein refers to a saturated carbocycle. Exemplarycarbocycles include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl,adamantyl, phenyl, indanyl, norbornane, and naphthyl. Carbocycles can beoptionally substituted by one or more substituents such as thosesubstituents described herein.

“Cycloalkyl” refers to a stable, partially or fully saturated,monocyclic or polycyclic carbocyclic ring, which can include fused (whenfused with an aryl or a heteroaryl ring, the cycloalkyl is bondedthrough a non-aromatic ring atom), bridged, or spiro ring systems.

Representative cycloalkyls include, but are not limited to, cycloalkylshaving from three to fifteen carbon atoms (C₃-C₁₅ cycloalkyl), fromthree to ten carbon atoms (C₃-C₁₀ cycloalkyl), from three to eightcarbon atoms (C₃-C₈ cycloalkyl), from three to six carbon atoms (C₃-C₆cycloalkyl), from three to five carbon atoms (C₃-C₅ cycloalkyl), orthree to four carbon atoms (C₃-C₄ cycloalkyl). In some embodiments, thecycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, thecycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkylsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocyclesinclude, for example, adamantyl, norbornyl, decalinyl,bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin,bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkylsinclude, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Unless stated otherwise specifically in the specification,a cycloalkyl is optionally substituted, for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, a cycloalkyl is optionally substituted with oxo,halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, a cycloalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, thecycloalkyl is optionally substituted with halogen.

“Cycloalkylalkyl” refers to a radical of the formula —R^(c)-cycloalkylwhere R^(c) is an alkylene chain as described above.

“Cycloalkylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-cycloalkyl where R^(c) is an alkylene chain asdescribed above.

“Halo” or “halogen” refers to halogen substituents such as bromo,chloro, fluoro and iodo substituents.

As used herein, the term “haloalkyl” or “haloalkane” refers to an alkylradical, as defined above, that is substituted by one or more halogenradicals, for example, trifluoromethyl, dichloromethyl, bromomethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Insome embodiments, the alkyl part of the fluoroalkyl radical isoptionally further substituted. Examples of halogen substituted alkanes(“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane,fluoromethane, iodomethane), di- and trihalomethane (e.g.,trichloromethane, tribromomethane, trifluoromethane, triiodomethane),1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane,2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane,2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitablecombinations of alkanes (or substituted alkanes) and halogens (e.g., Cl,Br, F, I, etc.). When an alkyl group is substituted with more than onehalogen radicals, each halogen can be independently selected e.g.,1-chloro,2-fluoroethane.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, for example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more hydroxyls. In some embodiments, the alkyl issubstituted with one hydroxyl. In some embodiments, the alkyl issubstituted with one, two, or three hydroxyls. Hydroxyalkyl include, forexample, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, orhydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

“Aminoalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more amines. In some embodiments, the alkyl issubstituted with one amine. In some embodiments, the alkyl issubstituted with one, two, or three amines. Aminoalkyl include, forexample, aminomethyl, aminoethyl, aminopropyl, aminobutyl, oraminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C₁-C₆heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atomsand one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.—NH—, —N(alkyl)-), sulfur, or combinations thereof wherein theheteroalkyl is attached to the rest of the molecule at a carbon atom ofthe heteroalkyl. Examples of such heteroalkyl are, for example,—CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃, or —CH(CH₃)OCH₃. Unlessstated otherwise specifically in the specification, a heteroalkyl isoptionally substituted for example, with oxo, halogen, amino, nitrile,nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, a heteroalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments,a heteroalkyl is optionally substituted with oxo, halogen, methyl,ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, the heteroalkyl isoptionally substituted with halogen.

“Heterocycloalkyl” refers to a stable 3- to 24-membered partially orfully saturated ring radical comprising 2 to 23 carbon atoms and atleast one ring heteroatoms. In some embodiments, a heterocycloalkylcontains from one to 8 heteroatoms selected from the group consisting ofnitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwisespecifically in the specification, the heterocycloalkyl radical can be amonocyclic, bicyclic, tricyclic, or tetracyclic ring system, which caninclude fused (when fused with an aryl or a heteroaryl ring, theheterocycloalkyl is bonded through a non-aromatic ring atom) or bridgedring systems; and the nitrogen, carbon, or sulfur atoms in theheterocycloalkyl radical can be optionally oxidized; the nitrogen atomcan be optionally quaternized.

Representative heterocycloalkyls include, but are not limited to,heterocycloalkyls having from two to fifteen carbon atoms (C₂-C₁₅heterocycloalkyl), from two to ten carbon atoms (C₂-C₁₀heterocycloalkyl), from two to eight carbon atoms (C₂-C₈heterocycloalkyl), from two to six carbon atoms (C₂-C₆heterocycloalkyl), from two to five carbon atoms (C₂-C₅heterocycloalkyl), or two to four carbon atoms (C₂-C₄ heterocycloalkyl).In some embodiments, the heterocycloalkyl is a 3- to 6-memberedheterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicalsinclude, but are not limited to, aziridinyl, azetidinyl, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl,3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ringforms of the carbohydrates, including but not limited to, themonosaccharides, the disaccharides, and the oligosaccharides. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, a heterocycloalkyl is optionally substituted, forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl,alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, a heterocycloalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, a heterocycloalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH,or —OMe. In some embodiments, the heterocycloalkyl is optionallysubstituted with halogen.

“Heterocycle” or “heterocyclyl” refers to a saturated, unsaturated oraromatic ring comprising one or more ring heteroatoms. Exemplaryheteroatoms include N, O, Si, P, B, and S atoms. Heterocycles includee.g., 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclicrings (such as spiro, fused, or bridged rings). Unless stated otherwisespecifically in the specification, the heterocyclyl radical is amonocyclic, bicyclic, tricyclic or tetracyclic ring system, whichoptionally includes fused, bridged, or spirocyclic ring systems. Theheteroatoms in the heterocyclyl radical are optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheterocyclyl radical can be partially or fully saturated. Theheterocyclyl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl.

Unless stated otherwise specifically in the specification, the term“heterocyclyl” is meant to include heterocyclyl radicals as definedabove that are optionally substituted. For example, a heterocyclyl canbe optionally substituted by one or more substituents by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—CN, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Heteroaryl” or “aromatic heterocycle” refers to a ring system radicalcomprising carbon atom(s) and one or more ring heteroatoms (e.g.,selected from the group consisting of nitrogen, oxygen, phosphorous,silicon, and sulfur), and at least one aromatic ring. In someembodiments, a heteroaryl is a 5- to 14-membered ring system radicalcomprising one to thirteen carbon atoms, one to six heteroatoms selectedfrom the group consisting of nitrogen, oxygen, phosphorous, and sulfur.The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, which can include fused (when fused with acycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through anaromatic ring atom) or bridged ring systems; and the nitrogen, carbon,or sulfur atoms in the heteroaryl radical can be optionally oxidized;the nitrogen atom can be optionally quaternized. In some embodiments,the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments,the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, butare not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl,benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl is optionallysubstituted, for example, with halogen, amino, nitrile, nitro, hydroxyl,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, aheteroaryl is optionally substituted with halogen, methyl, ethyl, —CN,—CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, a heteroaryl isoptionally substituted with halogen, methyl, ethyl, —CN, —CF₃, —OH, or—OMe. In some embodiments, the heteroaryl is optionally substituted withhalogen.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or substitutable heteroatoms, e.g.,NH, of the structure. It will be understood that “substitution” or“substituted with” includes the implicit proviso that such substitutionis in accordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound,i.e., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, etc. In certainembodiments, substituted refers to moieties having substituentsreplacing two hydrogen atoms on the same carbon atom, such assubstituting the two hydrogen atoms on a single carbon with an oxo,imino or thioxo group. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisdisclosure, the heteroatoms such as nitrogen can have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms.

In some embodiments, substituents can include any substituents describedherein, for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano(—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH₂),—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and alkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,cycloalkylalkyl, and heterocycle, any of which can be optionallysubstituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl,haloalkynyl, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino(═N—H), oximo (═N—OH), hydrazine (═N—NH₂), SFS, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R a)₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); wherein each R^(a) isindependently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each R^(a),valence permitting, can be optionally substituted with alkyl, alkenyl,alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo(═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazine(═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and wherein each R^(b) isindependently selected from a direct bond or a straight or branchedalkylene, alkenylene, or alkynylene chain, and each R^(c) is a straightor branched alkylene, alkenylene or alkynylene chain.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

The term “salt” or “pharmaceutically acceptable salt” refers to saltsderived from a variety of organic and inorganic counter ions well knownin the art. Pharmaceutically acceptable acid addition salts can beformed with inorganic acids and organic acids. Inorganic acids fromwhich salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Organic bases from which salts can be derivedinclude, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine.

In some embodiments, the pharmaceutically acceptable base addition saltis chosen from ammonium, potassium, sodium, calcium, and magnesiumsalts.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable excipient” or “pharmaceuticallyacceptable carrier” as used herein means a pharmaceutically acceptablematerial, composition or vehicle, such as a liquid or solid filler,diluent, excipient, solvent or encapsulating material. Each carrier mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient. Someexamples of materials which can serve as pharmaceutically acceptablecarriers include: (1) sugars, such as lactose, glucose and sucrose; (2)starches, such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

In certain embodiments, the term “prevent” or “preventing” as related toa disease or disorder can refer to a compound that, in a statisticalsample, reduces the occurrence of the disorder or condition in thetreated sample relative to an untreated control sample, or delays theonset or reduces the severity of one or more symptoms of the disorder orcondition relative to the untreated control sample.

The terms “treat,” “treating” or “treatment,” as used herein, caninclude alleviating, abating or ameliorating a disease or conditionsymptoms, preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease or condition,e.g., arresting the development of the disease or condition, relievingthe disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a compound disclosed hereinbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated, e.g., cancer or aninflammatory disease. In some embodiments, the result is a reductionand/or alleviation of the signs, symptoms, or causes of a disease, orany other desired alteration of a biological system.

For example, an “effective amount” for therapeutic uses is the amount ofthe composition comprising a compound disclosed herein required toprovide a clinically significant decrease in disease symptoms. In someembodiments, an appropriate “effective” amount in any individual case isdetermined using techniques, such as a dose escalation study.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group can be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc.).

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal.

Ranges provided herein are understood to be shorthand for all of thevalues within the range. For example, a range of 1 to 50 is understoodto include any number, combination of numbers, or sub-range from thegroup consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50,as well as all intervening decimal values between the aforementionedintegers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,and 1.9. With respect to sub-ranges, “nested sub-ranges” that extendfrom either end point of the range are specifically contemplated. Forexample, a nested sub-range of an exemplary range of 1 to 50 cancomprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

B. Compounds of the Disclosure

In one aspect, the disclosure provides a compound represented by Formula(IVa), or a pharmaceutically acceptable salt or solvate thereof:

wherein,

-   -   Y¹ is N or CR^(Y1);    -   Y² is N or CR^(Y2);    -   Y³ is N or CR^(Y3);    -   Y⁴ is N or CR^(Y4);

each of R¹ is independently selected from hydrogen, halo, —CN, —OR¹¹,—SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, andoptionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₈cycloalkyl, or optionally substituted C₂₋₇ heterocycloalkyl;

each of R⁴ and R^(4′) is independently selected from hydrogen, halo,—CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionallysubstituted C₂₋₇ heterocycloalkyl; or R⁴ and R^(4′) taken together forman oxo; or R⁴ and R^(4′) taken together with the carbon to which theyare attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl;

each of R⁵ and R^(5′) is independently selected from hydrogen, halo,—CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionallysubstituted C₂₋₇ heterocycloalkyl; or R⁵ and R^(5′) taken together forman oxo; or R⁵ and R^(5′) taken together with the carbon to which theyare attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl;

each of R⁶ and R^(6′) is independently selected from hydrogen, halo,—CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionallysubstituted C₂₋₇ heterocycloalkyl; or R⁶ and R^(6′) taken together forman oxo; or R⁶ and R^(6′) taken together with the carbon to which theyare attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl;

each of R⁸ and R⁹ is independently selected from hydrogen, halo, —CN,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionallysubstituted C₂₋₆ alkynyl; or R⁸ and R⁹ taken together with the carbon towhich they are attached form an optionally substituted 3-6 memberedcycloalkyl or heterocycloalkyl; ring A is monocyclic heteroaryl,bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclicheterocycloalkyl;

each of R^(A) is independently selected from halogen, —NO₂, oxo, CN,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),—N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),—N(R¹²)₂S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹); R¹¹ ishydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₁₋₆ heteroalkyl, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₇ heterocycloalkyl, optionally substituted phenyl,optionally substituted heteroaryl, optionally substituted —C₁₋₄alkylene-C₃₋₈ cycloalkyl, optionally substituted —C₁₋₄ alkylene-C₂₋₇heterocycloalkyl, optionally substituted —C₁₋₄ alkylene-phenyl, oroptionally substituted —C₁₋₄ alkylene-heteroaryl;

each of R¹² is independently selected from hydrogen, halogen, —OH, —NO₂,CN, C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₃₋₆ carbocycle, and 3- to 6-membered heterocycle, whereinthe C₃₋₆ carbocycle and 3- to 6-membered heterocycle is optionallysubstituted with one or more substituents independently selected fromhalogen, —OH, oxo, amino, —NO₂, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkyl;

R^(B1) is optionally substituted C₃₋₈ cycloalkyl, optionally substitutedC₂₋₉ heterocycloalkyl, optionally substituted naphthyl, optionallysubstituted phenyl, optionally substituted monocyclic heteroaryl, oroptionally substituted bicyclic heteroaryl;

each of R^(Y1), R^(Y2), R^(Y3) and R^(Y4) is independently selected fromhydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², C(O)OR¹², —OC(O)R¹²,—OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,—N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹¹,—S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₉ heterocycloalkyl, optionally substituted naphthyl,optionally substituted phenyl, optionally substituted monocyclicheteroaryl, and optionally substituted bicyclic heteroaryl; or

R^(Y1) and R^(Y2) are taken together with the carbons to which they areattached to form an optionally substituted C₃₋₈ cycloalkyl or optionallysubstituted C₂₋₉ heterocycloalkyl; or

R^(Y3) and R^(Y4) are taken together with the carbons to which they areattached to form an optionally substituted C₃₋₈ cycloalkyl or optionallysubstituted C₂₋₉ heterocycloalkyl;

m is 0, 1, 2, 3, or 4; and

p is 0 or 1.

In some embodiments of Formula (IVa), each of R⁴ and R^(4′) isindependently selected from hydrogen, halo, —CN, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionallysubstituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl; or R⁴ and R^(4′) taken together form an oxo; or R⁴ andR^(4′) taken together with the carbon to which they are attached form a3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. In someembodiments, each of R⁵ and R^(5′) is independently selected fromhydrogen, halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substitutedC₂₋₆ alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionallysubstituted C₂₋₇ heterocycloalkyl; or R⁵ and R^(5′) taken together forman oxo; or R⁵ and R^(5′) taken together with the carbon to which theyare attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl. In some embodiments, each of R⁶ and R^(6′) isindependently selected from hydrogen, halo, —CN, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionallysubstituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl; or R⁶ and R^(6′) taken together form an oxo; or R⁶ andR^(6′) taken together with the carbon to which they are attached form a3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

In some embodiments, the compound of Formula (IVa), (IVa-1), and(IVa-2),

-   -   Y¹ is N or CR^(Y1);    -   Y² is N or CR^(Y2)    -   Y³ is N or CR^(Y3);    -   Y⁴ is N or CR^(Y4);    -   each of R¹ is hydrogen, halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹),        optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆        heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionally        substituted C₂₋₆ alkynyl, optionally substituted C₃₋₈        cycloalkyl, or optionally substituted C₂₋₇ heterocycloalkyl;        -   wherein the alkyl, heteroalkyl, alkenyl, or alkynyl is            optionally substituted with one or more substituents            independently selected from: halogen, amino, oxo, —OH, —NO₂,            —CN, and C₁₋₃ alkoxyl;    -   each of R⁴ and R^(4′) is independently selected from hydrogen,        halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted        C₁₋₆ alkyl, optionally substituted C₁₋₆ alkenyl, optionally        substituted C₁₋₆ alkynyl, optionally substituted C₃₋₈        cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl, or        R⁴ and R^(4′) taken together form an oxo, or R⁴ and R^(4′) taken        together with the carbon to which they are attached form a 3-6        membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein        the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is        optionally substituted with one or more substituents        independently selected from: halogen, amino, —OH, —NO₂, oxo,        —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃ haloalkyl;    -   each of R⁵ and R^(5′) is independently selected from hydrogen,        halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted        C₁₋₆ alkyl, optionally substituted C₁₋₆ alkenyl, optionally        substituted C₁₋₆ alkynyl, optionally substituted C₃₋₈        cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl, or        R⁵ and R^(5′) taken together form an oxo, or R⁵ and R^(5′) taken        together with the carbon to which they are attached form a 3-6        membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein        the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is        optionally substituted with one or more substituents        independently selected from: halogen, amino, —OH, —NO₂, oxo,        —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃ haloalkyl;    -   each of R⁶ and R^(6′) is independently selected from hydrogen,        halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted        C₁₋₆ alkyl, optionally substituted C₁₋₆ alkenyl, optionally        substituted C₁₋₆ alkynyl, optionally substituted C₃₋₈        cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl, or        R⁶ and R^(6′) taken together form an oxo, or R⁶ and R^(6′) taken        together with the carbon to which they are attached form a 3-6        membered cycloalkyl or 3-6 membered heterocycloalkyl,        -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl or            heterocycloalkyl is optionally substituted with one or more            substituents independently selected from: halogen, amino,            —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃            haloalkyl;    -   each of R⁸ and R⁹ is independently selected from hydrogen, halo,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, and        optionally substituted C₂₋₆ alkynyl, or R⁸ and R⁹ taken together        with the carbon to which they are attached form an optionally        substituted 3-6 membered cycloalkyl or heterocycloalkyl,        -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl or            heterocycloalkyl is optionally substituted with one or more            substituents independently selected from: halogen, amino,            —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃            haloalkyl;    -   ring A is monocyclic heteroarylbicyclic heteroaryl, monocyclic        heterocycloalkyl, or bicyclic heterocycloalkyl;    -   each of R^(A) is independently selected from halogen, —NO₂, oxo,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally        substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈        cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, —OR¹¹,        —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,        —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹²,        —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)₂S(O)₂(R¹²),        —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹),        -   wherein the alkyl, alkenyl, alkynyl, heteroalkyl,            cycloalkyl, or heterocycloalkyl is optionally substituted            with one or more substituents independently selected from:            halogen, —OH, —NO₂, oxo, amino, —CN, C₁₋₆ alkoxyl, C₁₋₆            alkyl, C₁₋₆ haloalkyl, C₃₋₆ carbocycle, and 3- to 6-membered            heterocycle, wherein the C₃₋₆ carbocycle and 3- to            6-membered heterocycle is optionally substituted with one or            more substituents independently selected from halogen, —OH,            amino, —NO₂, oxo, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆            haloalkyl;    -   R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally        substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,        optionally substituted C₁₋₆ heteroalkyl, optionally substituted        C₃₋₈ cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl,        optionally substituted phenyl, optionally substituted        heteroaryl, optionally substituted —C₁₋₄ alkylene-C₃₋₈        cycloalkyl, optionally substituted —C₁₋₄ alkylene-C₂₋₇        heterocycloalkyl, optionally substituted —C₁₋₄ alkylene-phenyl,        or optionally substituted —C₁₋₄ alkylene-heteroaryl,        -   wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene,            cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is            optionally substituted with one or more substituents            independently selected from: halogen, —OH, amino, —NO₂, oxo,            C₁₋₆ alkoxy, —CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each of R¹² is independently selected from hydrogen, halogen,        —OH, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl,        C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₃₋₆ carbocycle, and 3- to        6-membered heterocycle, wherein the C₃₋₆ carbocycle and 3- to        6-membered heterocycle is optionally substituted with one or        more substituents independently selected from halogen, —OH, oxo,        amino, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl;    -   R^(B1) is optionally substituted C₃₋₈ cycloalkyl, optionally        substituted C₂₋₉ heterocycloalkyl, optionally substituted        naphthyl, optionally substituted phenyl, optionally substituted        monocyclic heteroaryl, or optionally substituted bicyclic        heteroaryl,        -   wherein each of the cycloalkyl, heterocycloalkyl, naphthyl,            phenyl or heteroaryl is optionally substituted with one or            more substituents independently selected from: halogen,            —NO₂, oxo, —CN, optionally substituted C₁₋₆ alkyl,            optionally substituted C₂₋₆ alkenyl, optionally substituted            C₂₋₆ alkynyl, optionally substituted C₁₋₆ heteroalkyl,            optionally substituted C₃₋₈ cycloalkyl, optionally            substituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹,            —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,            —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹²,            —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²),            —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹), wherein the            alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or            heterocycloalkyl is optionally substituted with one or more            substituents independently selected from: halogen, —OH,            —NO₂, amino, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, oxo, —CN,            C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃ haloalkyl;    -   each of R^(Y1), R^(Y2), R^(Y3) and R^(Y4) is independently        selected from hydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹,        —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally        substituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆        alkenyl, optionally substituted C₂₋₆ alkynyl, —OR¹¹, —SR¹¹,        —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹),        —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹²,        —S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl,        optionally substituted C₂₋₉ heterocycloalkyl, optionally        substituted naphthyl, optionally substituted phenyl, optionally        substituted monocyclic heteroaryl, and optionally substituted        bicyclic heteroaryl,        -   wherein the each of the alkyl, alkenyl, alkynyl,            heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl            or heteroaryl is optionally substituted with one or more            substituents independently selected from: halogen, —OH,            —NO₂, amino, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃            haloalkyl; or    -   R^(Y1) and R^(Y2) are taken together with the carbons to which        they are attached to form an optionally substituted C₃₋₈        cycloalkyl or optionally substituted C₂₋₉ heterocycloalkyl,        -   wherein the cycloalkyl or heterocycloalkyl is optionally            substituted with one or more substituents independently            selected from: halogen, —OH, amino, —NO₂, oxo, C₁₋₆ alkoxy,            —CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; or    -   R^(Y3) and R^(Y4) are taken together with the carbons to which        they are attached to form an optionally substituted C₃₋₈        cycloalkyl or optionally substituted C₂₋₉ heterocycloalkyl,        -   wherein the cycloalkyl or heterocycloalkyl is optionally            substituted with one or more substituents independently            selected from: halogen, —OH, amino, —NO₂, oxo, C₁₋₆ alkoxy,            —CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   m is 0, 1, 2, 3, or 4; and    -   p is 0 or 1.

In some embodiments of Formula (IVa), each of R⁴ and R^(4′) isindependently selected from hydrogen, halo, —CN, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionallysubstituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl, or R⁴ and R^(4′) taken together form an oxo, or R⁴ andR^(4′) taken together with the carbon to which they are attached form a3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl,

wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl isoptionally substituted with one or more substituents independentlyselected from: halogen, amino, —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃alkyl and C₁₋₃ haloalkyl.

In some embodiments of Formula (IVa), each of R⁵ and R^(5′) isindependently selected from hydrogen, halo, —CN, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionallysubstituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl, or R⁵ and R^(5′) taken together form an oxo, or R⁵ andR^(5′) taken together with the carbon to which they are attached form a3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl,

wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl isoptionally substituted with one or more substituents independentlyselected from: halogen, amino, —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃alkyl and C₁₋₃ haloalkyl.

In some embodiments of Formula (IVa), each of R⁶ and R^(6′) isindependently selected from hydrogen, halo, —CN, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionallysubstituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl, or R⁶ and R^(6′) taken together form an oxo, or R⁶ andR^(6′) taken together with the carbon to which they are attached form a3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein thealkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionallysubstituted with one or more substituents independently selected from:halogen, amino, —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃haloalkyl.

In some embodiments, the compound of Formula (IVa), (IVa-1), and(IVa-2),

-   -   Y¹ is N or CR^(Y1);    -   Y² is N or CR^(Y2)    -   Y³ is N or CR^(Y3);    -   Y⁴ is N or CR^(Y4);    -   each of R¹ is hydrogen, —CN, optionally substituted C₁₋₆ alkyl,        optionally substituted C₁₋₆ heteroalkyl, optionally substituted        C₂₋₆ alkenyl, and optionally substituted C₂₋₆ alkynyl,        optionally substituted C₃₋₈ cycloalkyl, or optionally        substituted C₂₋₇ heterocycloalkyl;        -   wherein the alkyl, heteroalkyl, alkenyl, or alkynyl is            optionally substituted with one or more substituents            independently selected from: halogen, amino, oxo, —OH, —NO₂,            —CN, and C₁₋₃ alkoxyl;    -   each of R⁴ and R^(4′) is independently selected from hydrogen,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally        substituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇        heterocycloalkyl, or R⁴ and R^(4′) taken together form an oxo,        or R⁴ and R^(4′) taken together with the carbon to which they        are attached form a 3-6 membered cycloalkyl or 3-6 membered        heterocycloalkyl,        -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl or            heterocycloalkyl is optionally substituted with one or more            substituents independently selected from: halogen, amino,            —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃            haloalkyl;    -   each of R⁵ and R^(5′) is independently selected from hydrogen,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally        substituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇        heterocycloalkyl, or R⁵ and R^(5′) taken together form an oxo,        or R⁵ and R^(5′) taken together with the carbon to which they        are attached form a 3-6 membered cycloalkyl or 3-6 membered        heterocycloalkyl,        -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl or            heterocycloalkyl is optionally substituted with one or more            substituents independently selected from: halogen, amino,            —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃            haloalkyl;    -   each of R⁶ and R^(6′) is independently selected from hydrogen,        halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted        C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally        substituted C₂₋₆ alkynyl, optionally substituted C₃₋₈        cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl, or        R⁶ and R^(6′) taken together form an oxo, or R⁶ and R^(6′) taken        together with the carbon to which they are attached form a 3-6        membered cycloalkyl or 3-6 membered heterocycloalkyl,        -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl or            heterocycloalkyl is optionally substituted with one or more            substituents independently selected from: halogen, amino,            —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃            haloalkyl;    -   each of R⁸ and R⁹ is independently selected from hydrogen, —CN,        optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆        heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionally        substituted C₂₋₆ alkynyl, or R⁸ and R⁹ taken together with the        carbon to which they are attached form an optionally substituted        3-6 membered cycloalkyl or heterocycloalkyl,        -   wherein the alkyl, alkenyl, alkynyl, cycloalkyl or            heterocycloalkyl is optionally substituted with one or more            substituents independently selected from: halogen, amino,            —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃            haloalkyl;    -   ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic        heterocycloalkyl, or bicyclic heterocycloalkyl;    -   each of R^(A) is independently selected from halogen, —NO₂, oxo,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally        substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈        cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, —OR¹¹,        —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,        —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹²,        —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)₂S(O)₂(R¹²),        —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹),        -   wherein the alkyl, alkenyl, alkynyl, heteroalkyl,            cycloalkyl, or heterocycloalkyl is optionally substituted            with one or more substituents independently selected from:            halogen, —OH, —NO₂, oxo, amino, —CN, C₁₋₆ alkoxyl, C₁₋₆            alkyl, C₁₋₆ haloalkyl, C₃₋₆ carbocycle, and 3- to 6-membered            heterocycle, wherein the C₃₋₆ carbocycle and 3- to            6-membered heterocycle is optionally substituted with one or            more substituents independently selected from halogen, —OH,            amino, —NO₂, oxo, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆            haloalkyl;    -   R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally        substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,        optionally substituted C₁₋₆ heteroalkyl, optionally substituted        C₃₋₈ cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl,        optionally substituted phenyl, optionally substituted        heteroaryl, optionally substituted —C₁₋₄ alkylene-C₃₋₈        cycloalkyl, optionally substituted —C₁₋₄ alkylene-C₂₋₇        heterocycloalkyl, optionally substituted —C₁₋₄ alkylene-phenyl,        or optionally substituted —C₁₋₄ alkylene-heteroaryl,        -   wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene,            cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is            optionally substituted with one or more substituents            independently selected from: halogen, —OH, amino, —NO₂, oxo,            C₁₋₆ alkoxy, —CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each of R¹² is independently selected from hydrogen, —NO₂, —CN,        C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl,        C₁₋₆ heteroalkyl, C₃₋₆ carbocycle, and 3- to 6-membered        heterocycle, wherein the C₃₋₆ carbocycle and 3- to 6-membered        heterocycle is optionally substituted with one or more        substituents independently selected from halogen, —OH, oxo,        amino, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl;    -   R^(B1) is optionally substituted C₃₋₈ cycloalkyl, optionally        substituted C₂₋₉ heterocycloalkyl, optionally substituted        naphthyl, optionally substituted phenyl, optionally substituted        monocyclic heteroaryl, or optionally substituted bicyclic        heteroaryl,        -   wherein each of the cycloalkyl, heterocycloalkyl, naphthyl,            phenyl or heteroaryl is optionally substituted with one or            more substituents independently selected from: halogen,            —NO₂, oxo, —CN, optionally substituted C₁₋₆ alkyl,            optionally substituted C₂₋₆ alkenyl, optionally substituted            C₂₋₆ alkynyl, optionally substituted C₁₋₆ heteroalkyl,            optionally substituted C₃₋₈ cycloalkyl, optionally            substituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹,            —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,            —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹²,            —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²),            —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹), wherein the            alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or            heterocycloalkyl is optionally substituted with one or more            substituents independently selected from: halogen, —OH,            —NO₂, amino, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, oxo, —CN,            C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃ haloalkyl;    -   each of R^(Y1), R^(Y2), R^(Y3) and R^(Y4) is independently        selected from hydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹,        —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally        substituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆        alkenyl, optionally substituted C₂₋₆ alkynyl, —OR¹¹, —SR¹¹,        —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹),        —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹²,        —S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl,        optionally substituted C₂₋₉ heterocycloalkyl, optionally        substituted naphthyl, optionally substituted phenyl, optionally        substituted monocyclic heteroaryl, and optionally substituted        bicyclic heteroaryl,        -   wherein the each of the alkyl, alkenyl, alkynyl,            heteroalkyl, cycloalkyl, heterocycloalkyl, naphthyl, phenyl            or heteroaryl is optionally substituted with one or more            substituents independently selected from: halogen, —OH,            —NO₂, amino, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃            haloalkyl; or    -   R^(Y1) and R^(Y2) are taken together with the carbons to which        they are attached to form an optionally substituted C₃₋₈        cycloalkyl or optionally substituted C₂₋₉ heterocycloalkyl,        wherein the cycloalkyl or heterocycloalkyl is optionally        substituted with one or more substituents independently selected        from: halogen, —OH, amino, —NO₂, oxo, C₁₋₆ alkoxy, —CN, C₁₋₆        alkyl, and C₁₋₆ haloalkyl; or    -   R^(Y3) and R^(Y4) are taken together with the carbons to which        they are attached to form an optionally substituted C₃₋₈        cycloalkyl or optionally substituted C₂₋₉ heterocycloalkyl,        wherein the cycloalkyl or heterocycloalkyl is optionally        substituted with one or more substituents independently selected        from: halogen, —OH, amino, —NO₂, oxo, C₁₋₆ alkoxy, —CN, C₁₋₆        alkyl, and C₁₋₆ haloalkyl;    -   m is 0, 1, 2, 3, or 4; and    -   p is 0 or 1.

In one aspect, the disclosure provides a compound represented by Formula(IVa), or a pharmaceutically acceptable salt or solvate thereof:

-   -   wherein,    -   Y¹ is N or CR^(Y1);    -   Y² is N or CR^(Y2)    -   Y³ is N or CR^(Y3);    -   Y⁴ is N or CR^(Y4);    -   R¹ is hydrogen, —CN, optionally substituted C₁₋₆ alkyl,        optionally substituted C₁₋₆ heteroalkyl, optionally substituted        C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally        substituted C₃₋₈ cycloalkyl, or optionally substituted C₂₋₇        heterocycloalkyl;    -   each of R⁴ and R^(4′) is independently selected from hydrogen,        halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted        C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally        substituted C₂₋₆ alkynyl, optionally substituted C₃₋₈        cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl; or        R⁴ and R^(4′) taken together form an oxo; or R⁴ and R^(4′) taken        together with the carbon to which they are attached form a 3-6        membered cycloalkyl or 3-6 membered heterocycloalkyl;    -   each of R⁵ and R^(5′) is independently selected from hydrogen,        halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted        C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally        substituted C₂₋₆ alkynyl, optionally substituted C₃₋₈        cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl; or        R⁵ and R^(5′) taken together form an oxo; or R⁵ and R^(5′) taken        together with the carbon to which they are attached form a 3-6        membered cycloalkyl or 3-6 membered heterocycloalkyl;    -   each of R⁶ and R^(6′) is independently selected from hydrogen,        halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), optionally substituted        C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally        substituted C₂₋₆ alkynyl, optionally substituted C₃₋₈        cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl; or        R⁶ and R^(6′) taken together form an oxo; or R⁶ and R^(6′) taken        together with the carbon to which they are attached form a 3-6        membered cycloalkyl or 3-6 membered heterocycloalkyl;    -   each of R⁸ and R⁹ is independently selected from hydrogen, halo,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, and        optionally substituted C₂₋₆ alkynyl; or R⁸ and R⁹ taken together        with the carbon to which they are attached form an optionally        substituted 3-6 membered cycloalkyl or 3-6 membered        heterocycloalkyl;    -   ring A is aryl, monocyclic heteroaryl, bicyclic heteroaryl,        monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl;    -   each of R^(A) is independently selected from halogen, —NO₂, oxo,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally        substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈        cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, —OR¹¹,        —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,        —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹²,        —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)₂S(O)₂(R¹²),        —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹);    -   R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally        substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,        optionally substituted C₁₋₆ heteroalkyl, optionally substituted        C₃₋₈ cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl,        optionally substituted phenyl, optionally substituted        heteroaryl, optionally substituted —C₁₋₄ alkylene-C₃₋₈        cycloalkyl, optionally substituted —C₁₋₄ alkylene-C₂₋₇        heterocycloalkyl, optionally substituted —C₁₋₄ alkylene-phenyl,        or optionally substituted —C₁₋₄ alkylene-heteroaryl;    -   each of R¹² is independently selected from hydrogen, —NO₂, —CN,        C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl,        C₁₋₆ heteroalkyl, C₃₋₆ carbocycle, and 3- to 6-membered        heterocycle, wherein the C₃₋₆ carbocycle and 3- to 6-membered        heterocycle is optionally substituted with one or more        substituents independently selected from halogen, —OH, oxo,        amino, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl;    -   R^(B1) is optionally substituted C₃₋₈ cycloalkyl, optionally        substituted C₂₋₉ heterocycloalkyl, optionally substituted        naphthyl, optionally substituted phenyl, optionally substituted        monocyclic heteroaryl, or optionally substituted bicyclic        heteroaryl;    -   each of R^(Y1), R^(Y2), R^(Y3) and R^(Y4) is independently        selected from hydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹,        —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally        substituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆        alkenyl, optionally substituted C₂₋₆ alkynyl, —OR¹¹, —SR¹¹,        —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹),        —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,        —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹²,        —S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl,        optionally substituted C₂₋₉ heterocycloalkyl, optionally        substituted naphthyl, optionally substituted phenyl, optionally        substituted monocyclic heteroaryl, and optionally substituted        bicyclic heteroaryl; or    -   R^(Y1) and R^(Y2) are taken together with the carbons to which        they are attached to form an optionally substituted C₃₋₈        cycloalkyl or optionally substituted C₂₋₉ heterocycloalkyl; or    -   R^(Y3) and R^(Y4) are taken together with the carbons to which        they are attached to form an optionally substituted C₃₋₈        cycloalkyl or optionally substituted C₂₋₉ heterocycloalkyl;    -   m is 0, 1, 2, 3, or 4; and    -   p is 0 or 1.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), ring A isaryl, monocyclic heteroaryl, bicyclic heteroaryl, monocyclicheterocycloalkyl, or bicyclic heterocycloalkyl, wherein when ring A isaryl, is

at least one of Y¹, Y², Y³, and Y⁴ is N; and

-   -   R^(B1) is optionally substituted monocyclic heteroaryl, or        optionally substituted bicyclic heteroaryl.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), ring A isaryl. In some embodiments, ring A is phenyl.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2),

In some embodiments, is

In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), ring A isunsubstituted aryl (e.g., phenyl). In some embodiments of Formulas(IVa), (IVa-1), and (IVa-2), ring A is aryl (e.g., phenyl) that isoptionally substituted with 1 to 5 R^(A). In some embodiments ofFormulas (IVa), (IVa-1), and (IVa-2), ring A is aryl (e.g., phenyl) thatis substituted with 1 R^(A). In some embodiments of Formulas (IVa),(IVa-1), and (IVa-2), ring A is aryl (e.g., phenyl) that is substitutedwith 2 R^(A). In some embodiments of Formulas (IVa), (IVa-1), and(IVa-2), ring A is aryl (e.g., phenyl) that is substituted with 3 R^(A).In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), ring A isaryl (e.g., phenyl) that is substituted with 4 R^(A). In someembodiments of Formulas (IVa), (IVa-1), and (IVa-2), ring A is aryl(e.g., phenyl) that is substituted with 5 R^(A).

In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), at leastone of Y¹, Y², Y³ and Y⁴ is N. In some embodiments, one of Y¹, Y², Y³,and Y⁴ is N. In some embodiments, two of Y¹, Y², Y³, and Y⁴ are N. Insome embodiments, three of Y¹, Y², Y³, and Y⁴ are N. In some embodimentsof Formulas (IVa), (IVa-1), and (IVa-2), R^(B1) is optionallysubstituted monocyclic heteroaryl, or optionally substituted bicyclicheteroaryl. In some embodiments, R^(B1) is optionally substitutedmonocyclic heteroaryl (e.g., 5 membered heteroaryl). In someembodiments, R^(B1) is substituted monocyclic heteroaryl.

In some embodiments of Formulas (IVa), (IVa-1), and (IVa-2), each R^(A)is independently selected from halogen, —NO₂, oxo, —CN, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₂₋₇heterocycloalkyl, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,—OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,—N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)₂S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and—S(O)₂N(R¹²)(R¹¹). In some embodiments, R^(A) is not C₁₋₆ alkoxyl. Insome embodiments, R^(A) is not Cl. In some embodiments, R^(A) is nothalogen.

In some embodiments, the compound of Formula (IVa) is represented byFormula (IVa-1), or a pharmaceutically acceptable salt or solvatethereof:

In some embodiments, the compound of Formula (IVa) is represented byFormula (IVa-2), or a pharmaceutically acceptable salt or solvatethereof:

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), each of R¹is hydrogen, —CN, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, andoptionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₈cycloalkyl, or optionally substituted C₂₋₇ heterocycloalkyl.

In some embodiments of Formula (IVa) and (IVa-1), each of R⁴ and R^(4′)is independently selected from hydrogen, —CN, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substitutedC₂₋₆ alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionallysubstituted C₂₋₇ heterocycloalkyl; or R⁴ and R^(4′) taken together forman oxo; or R⁴ and R^(4′) taken together with the carbon to which theyare attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl.

In some embodiments of Formula (IVa) and (IVa-1), each of R⁵ and R^(5′)is independently selected from hydrogen, —CN, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substitutedC₂₋₆ alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionallysubstituted C₂₋₇ heterocycloalkyl; or R⁵ and R^(5′) taken together forman oxo; or R⁵ and R^(5′) taken together with the carbon to which theyare attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl.

In some embodiments of Formula (IVa) and (IVa-1), each of R⁶ and R^(6′)is independently selected from hydrogen, —CN, optionally substitutedC₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substitutedC₂₋₆ alkynyl, optionally substituted C₃₋₈ cycloalkyl, and optionallysubstituted C₂₋₇ heterocycloalkyl; or R⁶ and R^(6′) taken together forman oxo; or R⁶ and R^(6′) taken together with the carbon to which theyare attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl.

In some embodiments of Formula (IVa), each of R⁸ and R⁹ is independentlyselected from hydrogen, —CN, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆alkenyl, and optionally substituted C₂₋₆ alkynyl; or R⁸ and R⁹ takentogether with the carbon to which they are attached form an optionallysubstituted 3-6 membered cycloalkyl or heterocycloalkyl.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), each of R¹²is independently selected from hydrogen, —NO₂, CN, C₁₋₆ alkyl, C₁₋₆aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₃₋₆carbocycle, and 3- to 6-membered heterocycle, wherein the C₃₋₆carbocycle and 3- to 6-membered heterocycle is optionally substitutedwith one or more substituents independently selected from halogen, —OH,oxo, amino, —NO₂, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), ring A is3-6 membered monocyclic heterocycloalkyl containing 1-4 heteroatomsselected from O, S, N, P, and Si. In some embodiments, ring A is fused,spiro, or bridged bicyclic heterocycloalkyl containing 1-4 heteroatomsselected from O, S, N, P, and Si. In some embodiments, ring A is a 5membered monocyclic heteroaryl. In some embodiments, ring A is a 6membered monocyclic heteroaryl. In some embodiments, ring A is a 6membered monocyclic heteroaryl containing 1-3 heteroatoms. In someembodiments, ring A is pyridine, pyrimidine, pyrazine, pyridazine,triazine, imidazole, pyrazole, triazole, oxazole, isoxazole, orthiophene. In some embodiments,

In some embodiments,

In some embodiments is

In some embodiments,

In some embodiments

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, ring A is bicyclic heteroaryl. In some embodiments,ring A is fused 5-6, 6-6, or 6-5 bicyclic heteroaryl.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), each R^(A)is independently selected from halogen, —NO₂, oxo, —CN, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₂₋₇heterocycloalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹²,—OC(O)R², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹²,—N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)₂S(O)₂(R¹²), —S(O)R¹²,—S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹). In some embodiments of Formula (IVa),(IVa-1), and (IVa-2), each R^(A) is independently selected from halogen,OH, —NO₂, oxo, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, and C₃₋₆ cycloalkyl. In some embodiments, each R^(A) isindependently selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxyl, C₁₋₆haloalkyl, and C₃₋₆ cycloalkyl. In some embodiments, each R^(A) isindependently selected from C₁₋₆ alkyl, C₁₋₆ alkoxyl, C₁₋₆ haloalkoxyl,C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl. In some embodiments, each R^(A) isindependently selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxyl, and C₃₋₆cycloalkyl, wherein the alkyl, alkoxyl and cycloalkyl is optionallysubstituted with one or more halogen (e.g., 1-3 fluorine). In someembodiments, each R^(A) is independently selected from methyl, ethyl,propyl, butyl, —O-methyl, —O-ethyl, —O-propyl, —O-butyl, cyclopropyl,CN, OH, —O—CHF₂, —O—CH₂F, CHF₂, CH₂F, and CF₃. In some embodiments,R^(A) is halogen. In some embodiments, R^(A) is —NO₂. In someembodiments, R^(A) is oxo. In some embodiments, R^(A) is —CN. In someembodiments, R^(A) is optionally substituted C₁₋₆ alkyl. In someembodiments, R^(A) is C₁-alkyl. In some embodiments, R^(A) is C₂ alkyl.In some embodiments, R^(A) is C₃ alkyl. In some embodiments, R^(A) isoptionally substituted C₁₋₆ heteroalkyl. In some embodiments, R^(A) isC₃ heteroalkyl. In some embodiments, R^(A) is optionally substitutedC₃₋₈ cycloalkyl. In some embodiments, R^(A) is C₃ cycloalkyl. In someembodiments, R^(A) is optionally substituted C₂₋₇ heterocycloalkyl. Insome embodiments, R^(A) is C₂ heterocycloalkyl. In some embodiments,R^(A) is —OR¹¹. In some embodiments, R^(A) is —SR¹¹. In someembodiments, R^(A) is —N(R¹²)(R¹¹). In some embodiments, R^(A) is—C(O)R¹². In some embodiments, R^(A) is —C(O)OR¹². In some embodiments,R^(A) is —OC(O)R¹². In some embodiments, R^(A) is —OC(O)N(R¹²)(R¹¹). Insome embodiments, R^(A) is —C(O)N(R¹²)(R¹¹) In some embodiments, R^(A)is —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹². In some embodiments, R^(A) is—N(R¹²)C(O)N(R¹²)(R¹¹). In some embodiments, R^(A) is—N(R¹²)₂S(O)₂(R¹²). In some embodiments, R^(A) is —S(O)R¹². In someembodiments, R^(A) is —S(O)₂R¹². In some embodiments, R^(A) is—S(O)₂N(R¹²)(R¹¹).

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), R^(A) isindependently substituted with one or more substituents independentlyselected from: halogen, —OH, —NO₂, amino, —CN, C₁₋₆ alkoxyl, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ carbocycle, and 3- to 6-membered heterocycle,wherein the C₃₋₆ carbocycle and 3- to 6-membered heterocycle isoptionally substituted with one or more substituents independentlyselected from halogen, —OH, amino, —NO₂, oxo, —CN, C₁₋₆ alkyl, C₁₋₆alkoxy, and C₁₋₆ haloalkyl.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2),

is selected from:

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments

In some embodiments,

In some embodiments,

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), p is 1. Insome embodiments, p is 0.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), each of R⁸and R⁹ is independently selected from hydrogen, halo, —CN, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₂₋₆ alkenyl, and optionally substituted C₂₋₆alkynyl. In some embodiments of Formula (IVa), (IVa-1), and (IVa-2),each of R⁸ and R⁹ is independently selected from hydrogen, —CN,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionallysubstituted C₂₋₆ alkynyl. In some embodiments. In some embodiments, R⁸and R⁹ taken together with the carbon to which they are attached form anoptionally substituted 3-6 membered cycloalkyl or heterocycloalkyl.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), R^(B1) isoptionally substituted C₃₋₈ cycloalkyl or optionally substituted phenyl.In some embodiments, R^(B1) is optionally substituted C₂₋₉heterocycloalkyl, optionally substituted monocyclic heteroaryl, oroptionally substituted bicyclic heteroaryl, each of which containing 1-4heteroatoms selected from O, S, N, P, and Si. In some embodiments,R^(B1) is optionally substituted C₃₋₈ cycloalkyl. In some embodiments,R^(B1) is C₃ cycloalkyl. In some embodiments, R^(B1) is C₅ cycloalkyl.In some embodiments, R^(B1) is C₆ cycloalkyl. In some embodiments,R^(B1) is optionally substituted phenyl. In some embodiments, R^(B1) isoptionally substituted C₂₋₉ heterocycloalkyl. In some embodiments,R^(B1) is C₃ heterocycloalkyl. In some embodiments, R^(B1) is C₅heterocycloalkyl. In some embodiments, R^(B1) is C₆ heterocycloalkyl. Insome embodiments, R^(B1) is optionally substituted monocyclicheteroaryl. In some embodiments, R^(B1) is optionally substitutedbicyclic heteroaryl. In some embodiments, R^(B1) is imidazole, pyrazole,triazole, or tetrazole, each of which optionally substituted. In someembodiments, R^(B1) is imidazole. In some embodiments, R^(B1) ispyrazole. In some embodiments, R^(B1) is triazole. In some embodiments,R^(B1) is tetrazole. In some embodiments, R^(B1) is optionallysubstituted fused 5-6, 6-6 or 6-5 heteroaryl. In some embodiments,R^(B1) is optionally substituted with one or more substituentsindependently selected from halogen, —NO₂, oxo, —CN, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₂₋₇heterocycloalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹²,—OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R²)(R¹), —N(R¹²)C(O)R¹²,—N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹²,—S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹), wherein the alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substitutedwith one or more substituents independently selected from: halogen, —OH,—NO₂, amino, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃ alkyl and C₁₋₃ haloalkyl. Insome embodiments, R^(B1) is optionally substituted with one or moresubstituents independently selected from halogen, —OR¹¹, —NO₂, oxo, —CN,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ aminoalkyl, optionally substitutedC₁₋₆ hydroxyalkyl, optionally substituted C₁₋₆ heteroalkyl, optionallysubstituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl. In some embodiments, R^(B1) is optionally substitutedwith one or more substituents independently selected from halogen,—OR¹¹, —NO₂, oxo, —CN, C₁₋₃ haloalkyl, C₁₋₃ alkyl, C₁₋₃ aminoalkyl, C₁₋₃hydroxyalkyl, optionally substituted C₁₋₄ heteroalkyl (e.g.,—CH₂C(═O)N(CH₃)₂), optionally substituted C₃₋₆ cycloalkyl, andoptionally substituted C₂₋₅ heterocycloalkyl. In some embodiments,R^(B1) is optionally substituted with one or more substituentsindependently selected from halogen, oxo, —CN, C₁₋₃ haloalkyl, C₁₋₃alkyl, C₁₋₃ aminoalkyl, C₁₋₃ hydroxyalkyl, C₃₋₆ cycloalkyl, and C₂₋₅heterocycloalkyl. In some embodiments, R^(B1) is optionally substitutedwith one or more substituents (e.g., 1, 2 or 3) independently selectedfrom C₁₋₃ haloalkyl and C₁₋₃ alkyl. In some embodiments, R^(B1) issubstituted with halogen. In some embodiments, R^(B1) is substitutedwith —OR¹¹. In some embodiments, R^(B1) is substituted with —NO₂. Insome embodiments, R^(B1) is substituted with oxo. In some embodiments,R^(B1) is substituted with —CN. In some embodiments, R^(B1) issubstituted with optionally substituted C₁₋₆ haloalkyl. In someembodiments, R^(B1) is substituted with optionally substituted C₁₋₆alkyl. In some embodiments, R^(B1) is substituted with optionallysubstituted C₁₋₆ aminoalkyl.

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), R^(B1) is

In some embodiments of Formula (IVa), (IVa-1), and (IVa-2), R^(B1) is

In some embodiments, R^(B1) is

In some embodiments, R^(B1) is

In some embodiments, R^(B1) is

In some embodiments, R^(B1) is

In some embodiments, R^(B1) is

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), Y¹ is N or CR^(Y1). In some embodiments, Y¹ is N. In someembodiments, Y¹ is CR^(Y1). In some embodiments, Y² is N. In someembodiments, Y² is CR^(Y2). In some embodiments, Y³ is N. In someembodiments, Y³ is CR^(Y3). In some embodiments, Y⁴ is N. In someembodiments, Y⁴ is CR^(Y4).

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R¹ is hydrogen, halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)₂, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₂₋₆ alkenyl, and optionally substituted C₂₋₆alkynyl. In some embodiments of a compound of Formula (IVa), (IVa-1),and (IVa-2), R¹ is hydrogen, —CN, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆alkenyl, and optionally substituted C₂₋₆ alkynyl. In some embodiments,R¹ is hydrogen. In some embodiments, R¹ is halo. In some embodiments, R¹is —CN. In some embodiments, R¹ is —OR¹¹. In some embodiments, R¹ is—SR¹¹. In some embodiments, R¹ is —N(R¹²)₂. In some embodiments, R¹ isoptionally substituted C₁₋₆ alkyl. In some embodiments, R¹ is C₁₋₃alkyl. In some embodiments, R¹ is methyl. In some embodiments, R¹ isethyl. In some embodiments, R¹ is CD₃. In some embodiments, R¹ isoptionally substituted C₁₋₆ heteroalkyl. In some embodiments, R¹ is C₁₋₃heteroalkyl. In some embodiments, R¹ is optionally substituted C₂₋₆alkenyl. In some embodiments, R¹ is C₂₋₃ alkenyl. In some embodiments,R¹ is optionally substituted C₂₋₆ alkynyl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R¹ is hydrogen, halo, —CN, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹),optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₂₋₆ alkenyl, optionally substitutedC₂₋₆ alkynyl, optionally substituted C₃₋₈ cycloalkyl, or optionallysubstituted C₂₋₇ heterocycloalkyl. In some embodiments of a compound ofFormula (IVa), (IVa-1), and (IVa-2), R¹ is hydrogen, —CN, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₈ cycloalkyl, or optionallysubstituted C₂₋₇ heterocycloalkyl. In some embodiments, R¹ is hydrogen.In some embodiments, R¹ is halo. In some embodiments, R¹ is —CN. In someembodiments, R¹ is —OR¹¹. In some embodiments, R¹ is —SR¹¹. In someembodiments, R¹ is —N(R¹²)(R¹¹). In some embodiments, R¹ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, R¹ is optionallysubstituted C₁₋₆ heteroalkyl. In some embodiments, R¹ is optionallysubstituted C₂₋₆ alkenyl. In some embodiments, R¹ is optionallysubstituted C₂₋₆ alkynyl. In some embodiments, R¹ is optionallysubstituted C₃₋₈ cycloalkyl. In some embodiments, R¹ is optionallysubstituted C₂₋₇ heterocycloalkyl.

In some embodiments of a compound of Formula (IVa) or (IVa-1), each ofR⁴ and R^(4′) is independently selected from hydrogen, halo, —CN, —OR¹¹,—SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl; or R⁴ and R^(4′) taken together form an oxo; or R⁴ andR^(4′) taken together with the carbon to which they are attached form a3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. In someembodiments of a compound of Formula (IVa) or (IVa-1), each of R⁴ andR^(4′) is independently selected from hydrogen, —CN, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃₋₈ cycloalkyl, andoptionally substituted C₂₋₇ heterocycloalkyl; or R⁴ and R^(4′) takentogether form an oxo; or R⁴ and R^(4′) taken together with the carbon towhich they are attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl. In some embodiments, R⁴ is hydrogen. In someembodiments, R⁴ is halo. In some embodiments, R⁴ is —CN. In someembodiments, R⁴ is —OR¹¹. In some embodiments, R⁴ is —SR¹¹. In someembodiments, R⁴ is —N(R¹²)(R¹¹). In some embodiments, R⁴ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, R⁴ is optionallysubstituted C₁₋₆ alkenyl. In some embodiments, R⁴ is optionallysubstituted C₂₋₆ alkenyl. In some embodiments, R⁴ is optionallysubstituted C₁₋₆ alkynyl. In some embodiments, R⁴ is optionallysubstituted C₂₋₆ alkynyl. In some embodiments, R⁴ is optionallysubstituted C₃₋₈ cycloalkyl. In some embodiments, R⁴ is optionallysubstituted C₂₋₇ heterocycloalkyl. In some embodiments, R^(4′) ishydrogen. In some embodiments, R^(4′) is halo. In some embodiments,R^(4′) is —CN. In some embodiments, R^(4′) is —OR¹¹. In someembodiments, R^(4′) is —SR¹¹. In some embodiments, R^(4′) is—N(R¹²)(R¹¹). In some embodiments, R^(4′) is optionally substituted C₁₋₆alkyl. In some embodiments, R^(4′) is optionally substituted C₁₋₆alkenyl. In some embodiments, R^(4′) is optionally substituted C₁₋₆alkynyl. In some embodiments, R^(4′) is optionally substituted C₂₋₆alkenyl. In some embodiments, R^(4′) is optionally substituted C₂₋₆alkynyl. In some embodiments, R^(4′) is optionally substituted C₃₋₈cycloalkyl. In some embodiments, R^(4′) is and optionally substitutedC₂₋₇ heterocycloalkyl. In some embodiments, R⁴ and R^(4′) taken togetherform an oxo. In some embodiments, R⁴ and R^(4′), taken together with thecarbon to which they are attached form a 3-6 membered cycloalkyl or 3-6membered heterocycloalkyl.

In some embodiments of a compound of Formula (IVa) or (IVa-1)), each ofR⁵ and R^(5′) is independently selected from hydrogen, halo, —CN, —OR¹¹,—SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl. In some embodiments of a compound of Formula (IVa) or(IVa-1)), each of R⁵ and R^(5′) is independently selected from hydrogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₃₋₈ cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl. Insome embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is halo. Insome embodiments, R⁵ is —CN. In some embodiments, R⁵ is —OR¹¹. In someembodiments, R⁵ is —SR¹¹. In some embodiments, R⁵ is —N(R¹²)(R¹¹). Insome embodiments, R⁵ is optionally substituted C₁₋₆ alkyl. In someembodiments, R⁵ is optionally substituted C₁₋₆ alkenyl. In someembodiments, R⁵ is optionally substituted C₁₋₆ alkynyl. In someembodiments, R⁵ is optionally substituted C₂₋₆ alkenyl. In someembodiments, R⁵ is optionally substituted C₂₋₆ alkynyl. In someembodiments, R⁵ is optionally substituted C₃₋₈ cycloalkyl. In someembodiments, R⁵ is optionally substituted C₂₋₇ heterocycloalkyl. In someembodiments, R^(5′) is hydrogen. In some embodiments, R^(5′) is halo. Insome embodiments, R^(5′) is —CN. In some embodiments, R^(5′) is —OR¹¹.In some embodiments, R^(5′) is —SR¹¹. In some embodiments, R^(5′) is—N(R¹²)(R¹¹). In some embodiments, R^(5′) is optionally substituted C₁₋₆alkyl. In some embodiments, R^(5′) is optionally substituted C₁₋₆alkenyl. In some embodiments, R^(5′) is optionally substituted C₁₋₆alkynyl. In some embodiments, R^(5′) is optionally substituted C₂₋₆alkenyl. In some embodiments, R^(5′) is optionally substituted C₂₋₆alkynyl. In some embodiments, R^(5′) is optionally substituted C₃₋₈cycloalkyl. In some embodiments, R^(5′) is and optionally substitutedC₂₋₇ heterocycloalkyl. In some embodiments, R⁵ and R^(5′) taken togetherform an oxo. In some embodiments, R⁵ and R^(5′) taken together with thecarbon to which they are attached form a 3-6 membered cycloalkyl or 3-6membered heterocycloalkyl.

In some embodiments of a compound of Formula (IVa) or (IVa-1), each ofR⁶ and R^(6′) is independently selected from hydrogen, halo, —CN, —OR¹¹,—SR¹¹, —N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₈ cycloalkyl, and optionally substituted C₂₋₇heterocycloalkyl. In some embodiments of a compound of Formula (IVa) or(IVa-1)), each of R⁶ and R^(6′) is independently selected from hydrogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₃₋₈ cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl. Insome embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is halo. Insome embodiments, R⁶ is —CN. In some embodiments, R⁶ is —OR¹¹. In someembodiments, R⁶ is —SR¹¹. In some embodiments, R⁶ is —N(R¹²)(R¹¹). Insome embodiments, R⁶ is optionally substituted C₁₋₆ alkyl. In someembodiments, R⁶ is optionally substituted C₁₋₆ alkenyl. In someembodiments, R⁶ is optionally substituted C₁₋₆ alkynyl. In someembodiments, R⁶ is optionally substituted C₂₋₆ alkenyl. In someembodiments, R⁶ is optionally substituted C₂₋₆ alkynyl. In someembodiments, R⁶ is optionally substituted C₃₋₈ cycloalkyl. In someembodiments, R⁶ is optionally substituted C₂₋₇ heterocycloalkyl. In someembodiments, R^(6′) is hydrogen. In some embodiments, R^(6′) is halo. Insome embodiments, R^(6′) is —CN. In some embodiments, R^(6′) is —OR¹¹.In some embodiments, R^(6′) is —SR¹¹. In some embodiments, R^(6′) is—N(R¹²)(R¹¹). In some embodiments, R^(6′) is optionally substituted C₁₋₆alkyl. In some embodiments, R^(6′) is optionally substituted C₁₋₆alkenyl. In some embodiments, R^(6′) is optionally substituted C₁₋₆alkynyl. In some embodiments, R^(6′) is optionally substituted C₂₋₆alkenyl. In some embodiments, R^(6′) is optionally substituted C₂₋₆alkynyl. In some embodiments, R^(6′) is optionally substituted C₃-8cycloalkyl. In some embodiments, R^(6′) is and optionally substitutedC₂₋₇ heterocycloalkyl. In some embodiments, R⁶ and R^(6′) taken togetherform an oxo. In some embodiments, R⁶ and R^(6′) taken together with thecarbon to which they are attached form a 3-6 membered cycloalkyl or 3-6membered heterocycloalkyl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), each of R⁸ and R⁹ is independently selected from hydrogen,halo, —CN, optionally substituted C₁₋₆ alkyl, optionally substitutedC₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionallysubstituted C₂₋₆ alkynyl. In some embodiments of a compound of Formula(IVa), (IVa-1), and (IVa-2), each of R⁸ and R⁹ is independently selectedfrom hydrogen, —CN, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, andoptionally substituted C₂₋₆ alkynyl. In some embodiments, R⁹ ishydrogen. In some embodiments, R⁸ is halo. In some embodiments, R⁸ is—CN. In some embodiments, R⁸ is optionally substituted C₁₋₆ alkyl. Insome embodiments, R⁸ is optionally substituted C₁₋₆ heteroalkyl. In someembodiments, R⁸ is optionally substituted C₂₋₆ alkenyl. In someembodiments, R⁸ is optionally substituted C₂₋₆ alkynyl. In someembodiments, R⁹ is hydrogen. In some embodiments, R⁹ is halo. In someembodiments, R⁹ is —CN. In some embodiments, R⁹ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, R⁹ is optionallysubstituted C₁₋₆ heteroalkyl. In some embodiments, R⁹ is optionallysubstituted C₂₋₆ alkenyl. In some embodiments, R⁹ is optionallysubstituted C₂₋₆ alkynyl. In some embodiments, R⁸ and R⁹ taken togetherwith the carbon to which they are attached form an optionallysubstituted 3-6 membered cycloalkyl or heterocycloalkyl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), ring A is monocyclic heteroaryl, bicyclic heteroaryl,monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl. In someembodiments, ring A is monocyclic heteroaryl. In some embodiments, ringA is bicyclic heteroaryl. In some embodiments, ring A is monocyclicheterocycloalkyl. In some embodiments, ring A is bicyclicheterocycloalkyl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), each of R^(A) is independently selected from halogen, —NO₂,oxo, CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₁₋₆ heteroalkyl, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),—N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),—N(R¹²)₂S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹). In someembodiments, R^(A) is halogen. In some embodiments, R^(A) is —NO₂. Insome embodiments, R^(A) is oxo. In some embodiments, R^(A) is CN. Insome embodiments, R^(A) is optionally substituted C₁₋₆ alkyl. In someembodiments, R^(A) is optionally substituted C₁₋₃ alkyl. In someembodiments, R^(A) is methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, t-butyl, —CF₃, —CH₂CF₃, or —CH₂CH₂F. In someembodiments, R^(A) is optionally substituted C₂₋₆ alkenyl. In someembodiments, R^(A) is optionally substituted C₂₋₆ alkynyl. In someembodiments, R^(A) is optionally substituted C₁₋₆ heteroalkyl. In someembodiments, R^(A) is optionally substituted C₃₋₈ cycloalkyl. In someembodiments, R^(A) is optionally substituted C₃₋₆ cycloalkyl, e.g.,cyclopropyl. In some embodiments, R^(A) is

In some embodiments, R^(A) is optionally substituted C₂₋₇heterocycloalkyl. In some embodiments, R^(A) is optionally substitutedC₂₋₅ heterocycloalkyl. In some embodiments, R^(A) is —OR¹¹. In someembodiments, R^(A) is —O—C₁₋₃ alkyl. In some embodiments, R^(A) is—OCH₃, —OCH₂CH₃, —OCH₂OMe, —OCH₂CH₂OH, —OC(CH₃)₃, or —OCH₂CH₂OCH₃. Insome embodiments, R^(A) is —OCH₃. In some embodiments, R^(A) is

In some embodiments, R^(A) is —SR¹¹. In some embodiments, R^(A) is—N(R¹²)(R¹¹). In some embodiments, R^(A) is —C(O)R¹². In someembodiments, R^(A) is C(O)OR¹². In some embodiments, R^(A) is —OC(O)R¹².In some embodiments, R^(A) is —OC(O)N(R¹²)(R¹¹). In some embodiments,R^(A) is —C(O)N(R¹²)(R¹¹). In some embodiments, R^(A) is —N(R¹²)C(O)R¹².In some embodiments, R^(A) is —N(R¹²)C(O)OR¹². In some embodiments,R^(A) is —N(R¹²)C(O)N(R¹²)(R¹¹). In some embodiments, R^(A) is—N(R¹²)₂S(O)₂(R¹²). In some embodiments, R^(A) is —S(O)R¹². In someembodiments, R^(A) is —S(O)₂R¹². In some embodiments, R^(A) is—S(O)₂N(R¹²)(R¹¹).

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, optionallysubstituted phenyl, optionally substituted heteroaryl, optionallysubstituted —C₁₋₄ alkylene-C₃₋₈ cycloalkyl, optionally substituted —C₁₋₄alkylene-C₂₋₇ heterocycloalkyl, optionally substituted —C₁₋₄alkylene-phenyl, or optionally substituted —C₁₋₄ alkylene-heteroaryl. Insome embodiments, R¹¹ is hydrogen. In some embodiments, R¹¹ isoptionally substituted C₁₋₆ alkyl. In some embodiments, R¹¹ isoptionally substituted C₁₋₃ alkyl. In some embodiments, R¹¹ is methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, —CF₃,—CH₂CF₃, or —CH₂CH₂F. In some embodiments, R¹¹ is optionally substitutedC₂₋₆ alkenyl. In some embodiments, R¹¹ is optionally substituted C₂₋₆alkynyl. In some embodiments, R¹¹ is optionally substituted C₁₋₆heteroalkyl. In some embodiments, R¹¹ is optionally substituted C₃₋₈cycloalkyl. In some embodiments, R¹¹ is optionally substituted C₂₋₇heterocycloalkyl. In some embodiments, R¹¹ is optionally substitutedphenyl. In some embodiments, R¹¹ is optionally substituted heteroaryl.In some embodiments, R¹¹ is optionally substituted —C₁₋₄ alkylene-C₃₋₈cycloalkyl. In some embodiments, R¹¹ is optionally substituted —C₁₋₄alkylene-C₂₋₇ heterocycloalkyl. In some embodiments, R¹¹ is optionallysubstituted —C₁₋₄ alkylene-phenyl. In some embodiments, R¹¹ isoptionally substituted —C₁₋₄ alkylene-heteroaryl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), each of R¹² is independently selected from hydrogen, halogen,—OH, —NO₂, CN, C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₆ heteroalkyl, C₃₋₆ carbocycle, and 3- to 6-memberedheterocycle, wherein the C₃₋₆ carbocycle and 3- to 6-memberedheterocycle is optionally substituted with one or more substituentsindependently selected from halogen, —OH, oxo, amino, —NO₂, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl. In some embodiments of acompound of Formula (IVa), (IVa-1), and (IVa-2), each of R¹² isindependently selected from hydrogen, —NO₂, CN, C₁₋₆ alkyl, C₁₋₆aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₃₋₆carbocycle, and 3- to 6-membered heterocycle, wherein the C₃₋₆carbocycle and 3- to 6-membered heterocycle is optionally substitutedwith one or more substituents independently selected from halogen, —OH,oxo, amino, —NO₂, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl. Insome embodiments, R¹² is hydrogen. In some embodiments, R¹² is halogen.In some embodiments, R¹² is —OH. In some embodiments, R¹² is —NO₂. Insome embodiments, R¹² is CN. In some embodiments, R¹² is C₁₋₆ alkyl. Insome embodiments, R¹² is C₁₋₆ aminoalkyl. In some embodiments, R¹² isC₁₋₆ hydroxyalkyl. In some embodiments, R¹² is C₁₋₆ haloalkyl. In someembodiments, R¹² is C₁₋₆ heteroalkyl. In some embodiments, R¹² is C₃₋₆carbocycle. In some embodiments, R¹² is and 3- to 6-memberedheterocycle, wherein the C₃₋₆ carbocycle and 3- to 6-memberedheterocycle is optionally substituted with one or more substituentsindependently selected from halogen, —OH, oxo, amino, —NO₂, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl. In some embodiments, the one ormore substituents is halogen. In some embodiments, the one or moresubstituents is —OH. In some embodiments, the one or more substituentsis oxo. In some embodiments, the one or more substituents is amino. Insome embodiments, the one or more substituents is —NO₂. In someembodiments, the one or more substituents is CN. In some embodiments,the one or more substituents is C₁₋₆ alkyl. In some embodiments, the oneor more substituents is C₁₋₆ alkoxy. In some embodiments, the one ormore substituents is C₁₋₆ haloalkyl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R^(B)t is optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₉ heterocycloalkyl, optionally substituted naphthyl,optionally substituted phenyl, optionally substituted monocyclicheteroaryl, or optionally substituted bicyclic heteroaryl. In someembodiments, R^(B1) is optionally substituted C₃₋₈ cycloalkyl. In someembodiments, R^(B1) is optionally substituted C₂₋₉ heterocycloalkyl. Insome embodiments, R^(B1) is optionally substituted 5-6 memberedheterocycloalkyl. In some embodiments, R^(B1) is optionally substitutednaphthyl. In some embodiments, R^(B1) is optionally substituted phenyl.In some embodiments, R^(B1) is optionally substituted monocyclicheteroaryl. In some embodiments, R^(B1) is optionally substitutedbicyclic heteroaryl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R^(Y)t is hydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,—C(O)OR¹, —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),—N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),—N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², —S(O)₂N(R¹²)(R¹¹), optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₂₋₉heterocycloalkyl, optionally substituted naphthyl, optionallysubstituted phenyl, optionally substituted monocyclic heteroaryl, andoptionally substituted bicyclic heteroaryl. In some embodiments, R^(Y1)is hydrogen. In some embodiments, R^(Y1) is halo. In some embodiments,R^(Y1) is —CN. In some embodiments, R^(Y1) is —NO₂. In some embodiments,R^(Y1) is —OR¹¹. In some embodiments, R^(Y1) is —SR¹¹. In someembodiments, R^(Y1) is —N(R¹²)(R¹¹). In some embodiments, R^(Y1) isoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(Y1) isoptionally substituted C₁₋₆ heteroalkyl. In some embodiments, R¹¹ isoptionally substituted C₂₋₆ alkenyl. In some embodiments, R^(Y1) isoptionally substituted C₂₋₆ alkynyl. In some embodiments, R^(Y1) is—OR¹¹. In some embodiments, R^(Y1) is —SR¹¹. In some embodiments, R^(Y1)is —N(R¹²)(R¹¹). In some embodiments, R^(Y1) is —C(O)R¹². In someembodiments, R^(Y1) is —C(O)OR¹². In some embodiments, R^(Y1) is—OC(O)R¹². In some embodiments, R^(Y1) is —OC(O)N(R¹²)(R¹¹). In someembodiments, R^(Y1) is —C(O)N(R¹²)(R¹¹). In some embodiments, R^(Y1) is—N(R¹²)C(O)R¹². In some embodiments, R^(Y1) is —N(R¹²)C(O)OR¹². In someembodiments, R^(Y1) is —N(R¹²)C(O)N(R¹²)(R¹¹). In some embodiments,R^(Y1) is —N(R¹²)S(O)₂(R¹²). In some embodiments, R^(Y1) is —S(O)R¹². Insome embodiments, R^(Y1) is —S(O)₂R¹². In some embodiments, R^(Y1) is—S(O)₂N(R¹²)(R¹¹). In some embodiments, R^(Y1) is optionally substitutedC₃₋₈ cycloalkyl. In some embodiments, R^(Y1) is optionally substitutedC₂₋₉ heterocycloalkyl. In some embodiments, R^(Y1) is optionallysubstituted naphthyl. In some embodiments, R^(Y1) is optionallysubstituted phenyl. In some embodiments, R^(Y1) is optionallysubstituted monocyclic heteroaryl. In some embodiments, R^(Y1) isoptionally substituted bicyclic heteroaryl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R^(Y2) is hydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,—C(O)OR¹, —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),—N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),—N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², —S(O)₂N(R¹²)(R¹¹), optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₂₋₉heterocycloalkyl, optionally substituted naphthyl, optionallysubstituted phenyl, optionally substituted monocyclic heteroaryl, andoptionally substituted bicyclic heteroaryl. In some embodiments, R^(Y2)is hydrogen. In some embodiments, R^(Y2) is halo. In some embodiments,R^(Y2) is —CN. In some embodiments, R^(Y2) is —NO₂. In some embodiments,R^(Y2) is —OR¹¹. In some embodiments, R^(Y2) is —SR¹¹. In someembodiments, R^(Y2) is —N(R¹²)(R¹¹). In some embodiments, R^(Y2) isoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(Y2) isoptionally substituted C₁₋₆ heteroalkyl. In some embodiments, R^(Y2) isoptionally substituted C₂₋₆ alkenyl. In some embodiments, R^(Y2) isoptionally substituted C₂₋₆ alkynyl. In some embodiments, R^(Y2) is—OR¹¹. In some embodiments, R^(Y2) is —SR¹¹. In some embodiments, R^(Y2)is —N(R¹²)(R¹¹). In some embodiments, R^(Y2) is —C(O)R¹². In someembodiments, R^(Y2) is —C(O)OR¹². In some embodiments, R^(Y2) is—OC(O)R¹². In some embodiments, R^(Y2) is —OC(O)N(R¹²)(R¹¹). In someembodiments, R^(Y2) is —C(O)N(R¹²)(R¹¹). In some embodiments, R^(Y2) is—N(R¹²)C(O)R¹². In some embodiments, R^(Y2) is —N(R¹²)C(O)OR¹². In someembodiments, R^(Y2) is —N(R¹²)C(O)N(R¹²)(R¹¹). In some embodiments,R^(Y2) is —N(R¹²)S(O)₂(R¹²). In some embodiments, R^(Y2) is —S(O)R¹². Insome embodiments, R^(Y2) is —S(O)₂R¹². In some embodiments, R¹² is—S(O)₂N(R¹²)(R¹¹). In some embodiments, R¹² is optionally substitutedC₃₋₈ cycloalkyl. In some embodiments, R^(Y2) is optionally substitutedC₂₋₉ heterocycloalkyl. In some embodiments, R^(Y2) is optionallysubstituted naphthyl. In some embodiments, R^(Y2) is optionallysubstituted phenyl. In some embodiments, R^(Y2) is optionallysubstituted monocyclic heteroaryl. In some embodiments, R^(Y2) isoptionally substituted bicyclic heteroaryl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R^(Y3) is hydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,—C(O)OR¹, —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R²)(R¹), —N(R¹²)C(O)R¹²,—N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹²,—S(O)₂R¹², —S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl,optionally substituted C₂₋₉ heterocycloalkyl, optionally substitutednaphthyl, optionally substituted phenyl, optionally substitutedmonocyclic heteroaryl, and optionally substituted bicyclic heteroaryl.In some embodiments, R^(Y3) is hydrogen. In some embodiments, R^(Y3) ishalo. In some embodiments, R^(Y3) is —CN. In some embodiments, R^(Y3) is—NO₂. In some embodiments, R^(Y3) is —OR¹¹. In some embodiments, R^(Y3)is —SR¹¹. In some embodiments, R^(Y3) is —N(R¹²)(R¹¹). In someembodiments, R^(Y3) is optionally substituted C₁₋₆ alkyl. In someembodiments, R^(Y3) is optionally substituted C₁₋₆ heteroalkyl. In someembodiments, R^(Y3) is optionally substituted C₂₋₆ alkenyl. In someembodiments, R^(Y3) is optionally substituted C₂₋₆ alkynyl. In someembodiments, R^(Y3) is —OR¹¹. In some embodiments, R^(Y3) is —SR¹¹. Insome embodiments, R^(Y3) is —N(R¹²)(R¹¹). In some embodiments, R^(Y3) is—C(O)R¹². In some embodiments, R^(Y3) is —C(O)OR¹². In some embodiments,R^(Y3) is —OC(O)R¹². In some embodiments, R^(Y3) is —OC(O)N(R¹²)(R¹¹).In some embodiments, R^(Y3) is —C(O)N(R¹²)(R¹¹). In some embodiments,R^(Y3) is —N(R¹²)C(O)R¹². In some embodiments, R^(Y3) is—N(R¹²)C(O)OR¹². In some embodiments, R^(Y3) is —N(R¹²)C(O)N(R¹²)(R¹¹).In some embodiments, R^(Y3) is —N(R¹²)S(O)₂(R¹²). In some embodiments,R^(Y3) is —S(O)R¹². In some embodiments, R^(Y3) is —S(O)₂R¹². In someembodiments, R^(Y3) is —S(O)₂N(R¹²)(R¹¹). In some embodiments, R^(Y3) isoptionally substituted C₃₋₈ cycloalkyl. In some embodiments, R^(Y3) isoptionally substituted C₂₋₉ heterocycloalkyl. In some embodiments,R^(Y3) is optionally substituted naphthyl. In some embodiments, R^(Y3)is optionally substituted phenyl. In some embodiments, R^(Y3) isoptionally substituted monocyclic heteroaryl. In some embodiments,R^(Y3) is optionally substituted bicyclic heteroaryl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R^(Y4) is hydrogen, halo, —CN, —NO₂, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), optionally substituted C₁₋₆ alkyl, optionally substitutedC₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,—C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R²)(R¹), —N(R¹²)C(O)R¹²,—N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹²,—S(O)₂R¹², —S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl,optionally substituted C₂₋₉ heterocycloalkyl, optionally substitutednaphthyl, optionally substituted phenyl, optionally substitutedmonocyclic heteroaryl, and optionally substituted bicyclic heteroaryl.In some embodiments, R^(Y4) is hydrogen. In some embodiments, R^(Y4) ishalo. In some embodiments, R^(Y4) is —CN. In some embodiments, R^(Y4) is—NO₂. In some embodiments, R^(Y4) is —OR¹¹. In some embodiments, R^(Y4)is —SR¹¹. In some embodiments, R^(Y4) is —N(R¹²)(R¹¹). In someembodiments, R^(Y4) is optionally substituted C₁₋₆ alkyl. In someembodiments, R^(Y4) is optionally substituted C₁₋₆ heteroalkyl. In someembodiments, R^(Y4) is optionally substituted C₂₋₆ alkenyl. In someembodiments, R^(Y4) is optionally substituted C₂₋₆ alkynyl. In someembodiments, R^(Y4) is —OR¹¹. In some embodiments, R^(Y4) is —SR¹¹. Insome embodiments, R^(Y4) is —N(R¹²)(R¹¹). In some embodiments, R^(Y4) is—C(O)R¹². In some embodiments, R^(Y4) is —C(O)OR¹². In some embodiments,R^(Y4) is —OC(O)R¹². In some embodiments, R^(Y4) is —OC(O)N(R¹²)(R¹¹).In some embodiments, R^(Y4) is —C(O)N(R¹²)(R¹¹). In some embodiments,R^(Y4) is —N(R¹²)C(O)R¹². In some embodiments, R^(Y4) is—N(R¹²)C(O)OR¹². In some embodiments, R^(Y4) is —N(R¹²)C(O)N(R¹²)(R¹¹).In some embodiments, R^(Y4) is —N(R¹²)S(O)₂(R¹²). In some embodiments,R^(Y4) is —S(O)R¹². In some embodiments, R^(Y4) is —S(O)₂R¹². In someembodiments, R^(Y4) is —S(O)₂N(R¹²)(R¹¹). In some embodiments, R^(Y4) isoptionally substituted C₃₋₈ cycloalkyl. In some embodiments, R^(Y4) isoptionally substituted C₂₋₉ heterocycloalkyl. In some embodiments,R^(Y4) is optionally substituted naphthyl. In some embodiments, R^(Y4)is optionally substituted phenyl. In some embodiments, R^(Y4) isoptionally substituted monocyclic heteroaryl. In some embodiments,R^(Y4) is optionally substituted bicyclic heteroaryl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), R^(Y1) and R^(Y2) are taken together with the carbons to whichthey are attached to form an optionally substituted C₃₋₈ cycloalkyl oroptionally substituted C₂₋₉ heterocycloalkyl. In some embodiments of acompound of Formula (IVa), (IVa-1), and (IVa-2), R^(Y3) and R^(Y4) aretaken together with the carbons to which they are attached to form anoptionally substituted C₃₋₈ cycloalkyl or optionally substituted C₂₋₉heterocycloalkyl.

In some embodiments of a compound of Formula (IVa), (IVa-1), and(IVa-2), m is 1, 2, 3, or 4. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments of a compound of Formula (IVa), (IVa-1), and (IVa-2)p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments of a compound of Formula (IVa-2), Y¹ is N orCR^(Y1); Y² is N or CR^(Y2); Y³ is CR^(Y3); Y⁴ is CR^(Y4); each ofR^(Y1), R^(Y2), R^(Y3), and R^(Y4) is independently hydrogen or C₁-C₆alkyl; R¹ is hydrogen or C₁-C₆ alkyl; p is 0;

and each R^(A) is independently OH, C₁₋₆ alkoxyl (e.g., —OCH₃), C₁₋₆alkyl, C₁₋₆ haloalkyl, or C₃-C₆ cycloalkyl (e.g., cyclopropyl); andR^(B1) is 5 membered heteroaryl optionally substituted with one or moresubstituents selected from C₁₋₃ haloalkyl and C₁₋₃ alkyl (e.g.,

In some embodiments, R^(B1) is substituted with 1 or 2 substituentsselected from C₁₋₃ haloalkyl and C₁₋₃ alkyl. In some embodiments, eachR^(A) is independently OH, C₁₋₃ alkyl, C₁₋₃ alkoxyl (e.g., —OCH₃), C₁₋₃haloalkyl, or C₃-C₆ cycloalkyl (e.g., cyclopropyl). In some embodiments,each R^(A) is independently C₁₋₃ alkoxyl (e.g., —OCH₃) or C₃-C₆cycloalkyl (e.g., cyclopropyl). In some embodiments, each R^(A) isindependently —OCH₃, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or cyclopropyl. In someembodiments, each R^(A) is independently C₁₋₃ alkoxyl, C₁₋₃ alkyl, C₁₋₃haloalkyl, or cyclopropyl. In some embodiments, —OCH₃ is —OCD₃.

In one aspect, described herein is a compound having the structure ofFormula (VI), or a salt or solvate thereof:

-   -   wherein,    -   ring C is phenyl or a 5 membered heteroaryl, wherein each of the        phenyl or heteroaryl is optionally substituted;    -   ring D is an aromatic, saturated or partially saturated 6        membered carbocycle or heterocycle, wherein each of the        carbocycle or heterocycle is optionally substituted;    -   each of R⁸ and R⁹ is independently selected from hydrogen, halo,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₁₋₆ heteroalkyl, optionally substituted C₂₋₆ alkenyl, and        optionally substituted C₂₋₆ alkynyl; or R⁸ and R⁹ taken together        form an oxo; or R⁸ and R⁹ taken together with the carbon to        which they are attached form an optionally substituted 3-6        membered cycloalkyl or heterocycloalkyl;    -   ring A is phenyl, naphthyl, monocyclic heteroaryl, bicyclic        heteroaryl, cycloalkyl, or heterocycloalkyl;    -   each of R^(A) is independently selected from halogen, —NO₂, oxo,        —CN, optionally substituted C₁₋₆ alkyl, optionally substituted        C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally        substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈        cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, —OR¹¹,        —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,        —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹²,        —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)₂S(O)₂(R¹²),        —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹);    -   R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl, optionally        substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,        optionally substituted C₁₋₆ heteroalkyl, optionally substituted        C₃₋₈ cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl,        optionally substituted phenyl, optionally substituted        heteroaryl, optionally substituted —C₁₋₄ alkylene-C₃₋₈        cycloalkyl, optionally substituted —C₁₋₄ alkylene-C₂₋₇        heterocycloalkyl, optionally substituted —C₁₋₄ alkylene-phenyl,        or optionally substituted —C₁₋₄ alkylene-heteroaryl;    -   each of R¹² is independently selected from hydrogen, halogen,        —OH, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl,        C₁₋₆ haloalkyl, and C₃₋₆ carbocycle, 3- to 6-membered        heterocycle, wherein the C₃₋₆ carbocycle and 3- to 6-membered        heterocycle is optionally substituted with one or more        substituents independently selected from halogen, —OH, oxo,        amino, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl;    -   R^(B) is hydrogen, halo, —CN, —NO₂, optionally substituted C₁₋₆        alkyl, optionally substituted C₂₋₆ alkenyl, optionally        substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆        heteroalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹²,        —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹²,        —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²),        —S(O)R¹², —S(O)₂R¹², —S(O)₂N(R¹²)(R¹¹), optionally substituted        C₃₋₈ cycloalkyl, optionally substituted C₂₋₉ heterocycloalkyl,        optionally substituted naphthyl, optionally substituted phenyl,        optionally substituted monocyclic heteroaryl, or optionally        substituted bicyclic heteroaryl; or    -   m is 0, 1, 2, 3, or 4; and    -   p is 0 or 1

In some embodiments of Formula (VI), each of R¹² is independentlyselected from hydrogen, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ haloalkyl, and C₃₋₆ carbocycle, 3- to 6-memberedheterocycle, wherein the C₃₋₆ carbocycle and 3- to 6-memberedheterocycle is optionally substituted with one or more substituentsindependently selected from halogen, —OH, oxo, amino, —NO₂, —CN, C₁₋₆alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl.

In some embodiments of Formula (VI), ring C is phenyl or a 5 memberedheteroaryl, wherein

each of the phenyl or heteroaryl is optionally substituted with 1, 2, 3,or 4 R^(1C), and each R^(1C) is independently halogen, —CN, —NO₂, —OH,—OR^(a), —OC(═O)R^(a), —OC(═O)OR, —OC(═O)NR^(c)R^(d), —SH, —SR^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —WC(═O)R^(a), —NR^(b)C(═O)OR, —NRS(═O)₂R^(a),—C(═O)R^(a), —C(═O)OR, —C(═O)NR^(c)R^(d), C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆heteroalkyl, C₂₋₆alkenyl,C₂-C₆alkynyl, C₃₋₈ cycloalkyl, C₂₋₇ heterocycloalkyl, aryl, orheteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is optionally and independentlysubstituted with one or more R^(1Ca);

ring D is an aromatic, saturated or partially saturated 6 memberedcarbocycle or heterocycle, wherein each of the carbocycle or heterocycleis optionally substituted with 1, 2, 3, 4 or 5, or 6 R^(1D), and

each R^(1D) is independently halogen, —CN, —NO₂, —OH, —OR^(a),—OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR,—NRS(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR, —C(═O)NR^(c)R^(d), C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆heteroalkyl,C₂₋₆alkenyl, C₂-C₆alkynyl, C₃₋₈ cycloalkyl, C₂₋₇ heterocycloalkyl, aryl,or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is optionally and independentlysubstituted with one or more R^(1Da);

each of R⁸ and R⁹ is independently selected from hydrogen, halo, —CN,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionallysubstituted C₂₋₆ alkynyl, or R⁸ and R⁹ taken together form an oxo, or R⁸and R⁹ taken together with the carbon to which they are attached form anoptionally substituted 3-6 membered cycloalkyl or heterocycloalkyl,wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl isoptionally substituted with one or more substituents independentlyselected from: halogen, amino, —OH, —NO₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃alkyl and C₁₋₃ haloalkyl;

each of R^(A) is independently selected from halogen, —NO₂, oxo, —CN,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,—C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),—N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),—N(R¹²)₂S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R¹²)(R¹¹), whereinthe alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, orheterocycloalkyl is optionally substituted with one or more substituentsindependently selected from: halogen, —OH, —NO₂, oxo, amino, —CN, C₁₋₆alkoxyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ carbocycle, and 3- to6-membered heterocycle, wherein the C₃₋₆ carbocycle and 3- to 6-memberedheterocycle is optionally substituted with one or more substituentsindependently selected from halogen, —OH, amino, —NO₂, oxo, —CN, C₁₋₆alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl;

R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, optionallysubstituted phenyl, optionally substituted heteroaryl, optionallysubstituted —C₁₋₄ alkylene-C₃₋₈ cycloalkyl, optionally substituted —C₁₋₄alkylene-C₂₋₇ heterocycloalkyl, optionally substituted —C₁₋₄alkylene-phenyl, or optionally substituted —C₁₋₄ alkylene-heteroaryl,wherein the alkyl, alkenyl, alkynyl, heteroalkyl, alkylene, cycloalkyl,heterocycloalkyl, phenyl, or heteroaryl is optionally substituted withone or more substituents independently selected from: halogen, —OH,amino, —NO₂, oxo, C₁₋₆ alkoxy, —CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

each of R¹² is independently selected from hydrogen, halogen, —OH, —NO₂,—CN, C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, andC₃₋₆ carbocycle, 3- to 6-membered heterocycle, wherein the C₃₋₆carbocycle and 3- to 6-membered heterocycle is optionally substitutedwith one or more substituents independently selected from halogen, —OH,oxo, amino, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl;

R^(B) is hydrogen, halo, —CN, —NO₂, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ heteroalkyl, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹),—C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,—N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹²,—S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₉ heterocycloalkyl, optionally substituted naphthyl,optionally substituted phenyl, optionally substituted monocyclicheteroaryl, or optionally substituted bicyclic heteroaryl, wherein eachof the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, naphthyl, phenyl or heteroaryl is optionallysubstituted with one or more substituents independently selected from:halogen, —NO₂, oxo, —CN, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹,—N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹),—C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,—N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and—S(O)₂N(R¹²)(R¹¹), wherein the alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, or heterocycloalkyl is optionally substituted with one ormore substituents independently selected from: halogen, —OH, —NO₂,amino, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, oxo, —CN, C₁₋₃ alkoxyl, C₁₋₃alkyl and C₁₋₃ haloalkyl;

each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,—C₁-C₆alkylene-cycloalkyl, —C₁-C₆alkylene-heterocycloalkyl,—C₁-C₆alkylene-aryl, or —C₁-C₆alkylene-heteroaryl; wherein each alkyl,alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,halogen, —CN, —OH, —OC₁-C₆alkyl, —S(═O)C₁-C₆alkyl, —S(═O)₂C₁-C₆alkyl,—S(═O)₂NH₂, —S(═O)₂NHC₁-C₆alkyl, —S(═O)₂N(C₁-C₆alkyl)₂, —NH₂,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —NHC(═O)OC₁-C₆alkyl, —C(═O)C₁-C₆alkyl,—C(═O)OH, —C(═O)OC₁-C₆alkyl, —C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂,—C(═O)NHC₁-C₆alkyl, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

each R^(b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,—C₁-C₆alkylene-cycloalkyl, —C₁-C₆alkylene-heterocycloalkyl,—C₁-C₆alkylene-aryl, or —C₁-C₆alkylene-heteroaryl; wherein each alkyl,alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,halogen, —CN, —OH, —OC₁-C₆alkyl, —S(═O)C₁-C₆alkyl, —S(═O)₂C₁-C₆alkyl,—S(═O)₂NH₂, —S(═O)₂NH C₁-C₆alkyl, —S(═O)₂N(C₁-C₆alkyl)₂, —NH₂,—NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —NHC(═O)OC₁-C₆alkyl, —C(═O)C₁-C₆alkyl,—C(═O)OH, —C(═O)OC₁-C₆alkyl, —C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂,—C(═O)NHC₁-C₆alkyl, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

each R^(c) and R^(d) are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylene-cycloalkyl, —C₁-C₆alkylene-heterocycloalkyl,—C₁-C₆alkylene-aryl, or —C₁-C₆alkylene-heteroaryl; wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, halogen, —CN,—OH, —OC₁-C₆alkyl, —S(═O)C₁-C₆alkyl, —S(═O)₂C₁-C₆alkyl, —S(═O)₂NH₂,—S(═O)₂NHC₁-C₆alkyl, —S(═O)₂N(C₁-C₆alkyl)₂, —NH₂, —NHC₁-C₆alkyl,—N(C₁-C₆alkyl)₂, —NHC(═O)OC₁-C₆alkyl, —C(═O) C₁-C₆alkyl, —C(═O)OH,—C(═O)OC₁-C₆alkyl, —C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂, —C(═O)NHC₁-C₆alkyl,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, orC₁-C₆heteroalkyl;

or R^(c) and R^(d) are taken together with the atom to which they areattached to form a heterocycloalkyl optionally substituted with one ormore oxo, halogen, —CN, —OH, —OC₁-C₆alkyl, —S(═O)C₁-C₆alkyl,—S(═O)₂C₁-C₆alkyl, —S(═O)₂NH₂, —S(═O)₂NHC₁-C₆alkyl,—S(═O)₂N(C₁-C₆alkyl)₂, —NH₂, —NHC₁-C₆alkyl, —N(C₁-C₆alkyl)₂,—NHC(═O)OC₁-C₆alkyl, —C(═O) C₁-C₆alkyl, —C(═O)OH, —C(═O)OC₁-C₆alkyl,—C(═O)NH₂, —C(═O)N(C₁-C₆alkyl)₂, —C(═O)NHC₁-C₆alkyl, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

each R^(1Ca) and R^(1Da) is independently halogen, —CN, —NO₂, —OH,—OR^(a), —OC(═O)R^(a), —OC(═O)OR, —OC(═O)NR^(c)R^(d), —SH, —SR^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR,—NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

m is 0, 1, 2, 3, or 4; and

p is 0 or 1.

In some embodiments of Formula (VI), ring C is 5 membered heteroaryl andring D is 6 membered heteroaryl. In some embodiments, ring C is 5membered heteroaryl and ring D is 6 membered heterocycloalkyl.

In some embodiments of Formula (VI), each of ring C and ring D isindependently optionally substituted with one or more substituentsselected from halo, —CN, —OR^(a), —SH, —SR^(a), —NR^(c)R^(d), optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₂₋₆ alkenyl, and optionally substituted C₂₋₆alkynyl, and wherein the alkyl, heteroalkyl, alkenyl, or alkynyl isoptionally substituted with one or more substituents independentlyselected from: halogen, amino, oxo, —OH, —NO₂, —CN, and C₁₋₃ alkoxyl.

In some embodiments of Formula (VI),

In some embodiments of Formula (VI), ring A is phenyl. In someembodiments, ring A is naphthyl. In some embodiments, ring A is 5 or 6membered monocyclic heteroaryl. In some embodiments, ring A is a 6membered monocyclic heteroaryl containing 1-3 heteroatoms.

In some embodiments of Formula (VI), ring A is pyridine, pyrimidine,pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole,isoxazole, or thiophene. In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments of Formula (VI), ring A is aryl. In someembodiments, ring A is phenyl. In some embodiments of Formula (VI),

In some embodiments,

In some embodiments of Formula (VI), ring A is unsubstituted aryl (e.g.,phenyl). In some embodiments of Formula (VI), ring A is aryl (e.g.,phenyl) that is optionally substituted with 1 to 5 R^(A). In someembodiments of Formula (VI), ring A is aryl (e.g., phenyl) that issubstituted with 1 R^(A). In some embodiments of Formula (VI), ring A isaryl (e.g., phenyl) that is substituted with 2 R^(A). In someembodiments of Formula (VI), ring A is aryl (e.g., phenyl) that issubstituted with 3 R^(A). In some embodiments of Formula (VI), ring A isaryl (e.g., phenyl) that is substituted with 4 R^(A). In someembodiments of Formula (VI), ring A is aryl (e.g., phenyl) that issubstituted with 5 R^(A).

In some embodiments of Formula (VI), ring A is bicyclic heteroaryl. Insome embodiments, ring A is fused 5-6, 6-6, or 6-5 bicyclic heteroaryl.

In some embodiments of Formula (VI), each of R^(A) is independentlyselected from halogen, —NO₂, oxo, —CN, optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆ heteroalkyl, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, —OR¹¹,—SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹),—C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,—N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)₂S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and—S(O)₂N(R¹²)(R¹¹). In some embodiments, each R^(A) is independentlysubstituted with one or more substituents independently selected from:halogen, —OH, —NO₂, amino, —CN, C₁. 6 alkoxyl, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ carbocycle, and 3- to 6-membered heterocycle, whereinthe C₃₋₆ carbocycle and 3- to 6-membered heterocycle is optionallysubstituted with one or more substituents independently selected fromhalogen, —OH, amino, —NO₂, oxo, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkyl.

In some embodiments of Formula (VI),

is selected from

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments of Formula (VI), p is 0. In some embodiments, p is1.

In some embodiments of Formula (VI), each of R⁸ and R⁹ is independentlyselected from hydrogen, halo, —CN, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆alkenyl, and optionally substituted C₂₋₆ alkynyl. In some embodiments ofFormula (VI), each of R⁸ and R⁹ is independently selected from hydrogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionallysubstituted C₂₋₆ alkynyl.

In some embodiments of Formula (VI), R⁸ and R⁹ taken together form anoxo.

In some embodiments of Formula (VI), R⁸ and R⁹ taken together with thecarbon to which they are attached form an optionally substituted 3-6membered cycloalkyl or heterocycloalkyl.

In some embodiments of Formula (VI), R^(B) is halo, —CN, —NO₂,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆heteroalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,—OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,—N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹²,—S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₉ heterocycloalkyl, optionally substituted phenyl,optionally substituted monocyclic heteroaryl, or optionally substitutedbicyclic heteroaryl. In some embodiments, R^(B) is optionallysubstituted 5 membered monocyclic heteroaryl with 1 to 4 heteroatomsselected from N, O, S and P. In some embodiments, R^(B) is imidazole,pyrazole, triazole, or tetrazole, each of which optionally substituted.In some embodiments, R^(B) is optionally substituted fused 5-6, 6-6 or6-5 heteroaryl.

In some embodiments of Formula (VI), R^(B) is optionally substitutedwith one or more substituents independently selected from halogen, —NO₂,oxo, —CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₇ heterocycloalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹²,—C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹),—N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)(R¹¹),—N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and —S(O)₂N(R²)(R¹¹), whereinthe alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, orheterocycloalkyl is optionally substituted with one or more substituentsindependently selected from: halogen, —OH, —NO₂, amino, oxo, —CN, C₁₋₃alkoxyl, C₁₋₃ alkyl and C₁₋₃ haloalkyl. In some embodiments, R^(B) isoptionally substituted with one or more substituents independentlyselected from halogen, —OR¹¹, —NO₂, oxo, —CN, optionally substitutedC₁₋₆ haloalkyl, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ aminoalkyl, optionally substituted C₁₋₆ hydroxyalkyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₃₋₈cycloalkyl, and optionally substituted C₂₋₇ heterocycloalkyl. In someembodiments, R^(B) is optionally substituted with one or moresubstituents independently selected from halogen, —OR¹¹, —NO₂, oxo, —CN,C₁₋₃ haloalkyl, C₁₋₃ alkyl, C₁₋₃ aminoalkyl, C₁₋₃ hydroxyalkyl,optionally substituted C₁₋₄ heteroalkyl (e.g., —CH₂C(═O)N(CH₃)₂),optionally substituted C₃₋₆ cycloalkyl, and optionally substituted C₂₋₅heterocycloalkyl. In some embodiments, R^(B) is optionally substitutedC₃₋₈ cycloalkyl. In some embodiments, R^(B) is C₃ cycloalkyl. In someembodiments, R^(B) is C₅ cycloalkyl. In some embodiments, R^(B) is C₆cycloalkyl. In some embodiments, R^(B) is optionally substituted phenyl.In some embodiments, R^(B) is optionally substituted C₂₋₉heterocycloalkyl. In some embodiments, R^(B) is C₃ heterocycloalkyl. Insome embodiments, R^(B) is C₅ heterocycloalkyl. In some embodiments,R^(B) is C₆ heterocycloalkyl. In some embodiments, R^(B) is optionallysubstituted 5-6 membered heterocycloalkyl or heteroaryl. In someembodiments, R^(B) is optionally substituted monocyclic heteroaryl. Insome embodiments, R^(B) is optionally substituted bicyclic heteroaryl.In some embodiments, R^(B) is imidazole, pyrazole, triazole, ortetrazole, each of which optionally substituted. In some embodiments,R^(B) is imidazole. In some embodiments, R^(B) is pyrazole. In someembodiments, R^(B) is triazole. In some embodiments, R^(B) is tetrazole.

In some embodiments of Formula (VI), R^(B) is selected from:

In some embodiments of Formula (VI), R^(B) is

In some embodiments R^(B) is

In some embodiments, R^(B) is

In some embodiments, R^(B) is

In some embodiments, R^(B) is

In some embodiments, R^(B) is

In some embodiments, R^(B) is

In some embodiments of Formula (VI), ring C is a 5 membered heteroaryl,wherein the heteroaryl is optionally substituted. In some embodiments,ring C is optionally substituted 5 membered heteroaryl.

In some embodiments of Formula (VI), ring D is an aromatic, saturated orpartially saturated 6 membered carbocycle or heterocycle, wherein eachof the carbocycle or heterocycle is optionally substituted. In someembodiments, ring D is an optionally substituted aromatic 6 memberedcarbocycle. In some embodiments, ring D is an optionally substitutedaromatic 6 membered heterocycle. In some embodiments, ring D is anoptionally substituted saturated 6 membered carbocycle. In someembodiments, ring D is an optionally substituted saturated 6 memberedheterocycle. In some embodiments, ring D is an optionally substitutedpartially saturated 6 membered carbocycle. In some embodiments, ring Dis an optionally substituted partially saturated 6 membered heterocycle.

In some embodiments of Formula (VI), each of R⁸ and R⁹ is independentlyselected from hydrogen, halo, —CN, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ heteroalkyl, optionally substituted C₂₋₆alkenyl, and optionally substituted C₂₋₆ alkynyl. In some embodiments ofFormula (VI), each of R⁸ and R⁹ is independently selected from hydrogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆heteroalkyl, optionally substituted C₂₋₆ alkenyl, and optionallysubstituted C₂₋₆ alkynyl. In some embodiments, R⁸ is hydrogen. In someembodiments, R⁸ is halo. In some embodiments, R⁸ is —CN. In someembodiments, R⁸ is optionally substituted C₁₋₆ alkyl. In someembodiments, R⁸ is optionally substituted C₁₋₆ heteroalkyl. In someembodiments, R⁸ is optionally substituted C₂₋₆ alkenyl. In someembodiments, R⁸ is optionally substituted C₂₋₆ alkynyl. In someembodiments, R⁹ is hydrogen. In some embodiments, R⁹ is halo. In someembodiments, R⁹ is —CN. In some embodiments, R⁹ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, R⁹ is optionallysubstituted C₁₋₆ heteroalkyl. In some embodiments, R⁹ is optionallysubstituted C₂₋₆ alkenyl. In some embodiments, R⁹ is optionallysubstituted C₂₋₆ alkynyl. In some embodiments, R⁸ and R⁹ taken togetherform an oxo. In some embodiments, R⁸ and R⁹ taken together with thecarbon to which they are attached form an optionally substituted 3-6membered cycloalkyl or heterocycloalkyl.

In some embodiments of Formula (VI), ring A is phenyl, naphthyl,monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, ringA is phenyl. In some embodiments, ring A is naphthyl. In someembodiments, ring A is monocyclic heteroaryl. In some embodiments, ringA is or bicyclic heteroaryl.

In some embodiments of Formula (VI), R^(A) is independently selectedfrom halogen, —NO₂, oxo, —CN, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆ heteroalkyl, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₂₋₇ heterocycloalkyl, —OR¹¹,—SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)N(R¹²)(R¹¹),—C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,—N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)₂S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹², and—S(O)₂N(R¹²)(R¹¹). In some embodiments, R^(A) is halogen. In someembodiments, R^(A) is —NO₂. In some embodiments, R^(A) is oxo. In someembodiments, R^(A) is —CN. In some embodiments, R^(A) is optionallysubstituted C₁₋₆ alkyl. In some embodiments, R^(A) is optionallysubstituted C₁₋₃ alkyl. In some embodiments, R^(A) is methyl, ethyl,propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, —CF₃,—CH₂CF₃, or —CH₂CH₂F. In some embodiments, R^(A) is optionallysubstituted C₂₋₆ alkenyl. In some embodiments, R^(A) is optionallysubstituted C₂₋₆ alkynyl. In some embodiments, R^(A) is optionallysubstituted C₁₋₆ heteroalkyl. In some embodiments, R^(A) is optionallysubstituted C₃₋₈cycloalkyl. In some embodiments, R^(A) is optionallysubstituted C₃₋₆ cycloalkyl, e.g., cyclopropyl. In some embodiments,R^(A) is

In some embodiments, R^(A) is optionally substituted C₂₋₇heterocycloalkyl. In some embodiments, R^(A) is optionally substitutedC₂₋₅ heterocycloalkyl. In some embodiments, R^(A) is —OR¹¹. In someembodiments, R^(A) is —O—C₁₋₃ alkyl. In some embodiments, R^(A) is—OCH₃, —OCH₂CH₃, —OCH₂OMe, —OCH₂CH₂OH, —OC(CH₃)₃, or —OCH₂CH₂OCH₃. Insome embodiments, R^(A) is —OCH₃. In some embodiments, R^(A) is

In some embodiments, R^(A) is —SR¹¹. In some embodiments, R^(A) is—N(R¹²)(R¹¹). In some embodiments, R^(A) is —C(O)R¹². In someembodiments, R^(A) is —C(O)OR¹². In some embodiments, R^(A) is—OC(O)R¹². In some embodiments, R^(A) is —OC(O)N(R¹²)(R¹¹). In someembodiments, R^(A) is —C(O)N(R¹²)(R¹¹). In some embodiments, R^(A) is—N(R¹²)C(O)R¹². In some embodiments, R^(A) is —N(R¹²)C(O)OR¹². In someembodiments, R^(A) is —N(R¹²)C(O)N(R¹²)(R¹¹). In some embodiments, R^(A)is —N(R¹²)₂S(O)₂(R¹²). In some embodiments, R^(A) is —S(O)R¹². In someembodiments, R^(A) is —S(O)₂R¹². In some embodiments, R^(A) is—S(O)₂N(R¹²)(R¹¹). In some embodiments, —OCH₃ is —OCD₃.

In some embodiments of Formula (VI), R¹¹ is hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₁₋₆ heteroalkyl,optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₂₋₇heterocycloalkyl, optionally substituted phenyl, optionally substitutedheteroaryl, optionally substituted —C₁₋₄ alkylene-C₃₋₈ cycloalkyl,optionally substituted —C₁₋₄ alkylene-C₂₋₇ heterocycloalkyl, optionallysubstituted —C₁₋₄ alkylene-phenyl, or optionally substituted —C₁₋₄alkylene-heteroaryl. In some embodiments, R¹¹ is hydrogen. In someembodiments, R¹¹ is optionally substituted C₁₋₆ alkyl. In someembodiments, R¹¹ is optionally substituted C₁₋₃ alkyl. In someembodiments, R^(A) is methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, t-butyl, —CF₃, —CH₂CF₃, or —CH₂CH₂F. In someembodiments, R¹¹ is optionally substituted C₂₋₆ alkenyl. In someembodiments, R¹¹ is optionally substituted C₂₋₆ alkynyl. In someembodiments, R¹¹ is optionally substituted C₁₋₆ heteroalkyl. In someembodiments, R¹¹ is optionally substituted C₃₋₈ cycloalkyl. In someembodiments, R¹¹ is optionally substituted C₂₋₇ heterocycloalkyl. Insome embodiments, R¹¹ is optionally substituted phenyl. In someembodiments, R¹¹ is optionally substituted heteroaryl. In someembodiments, R¹¹ is optionally substituted —C₁₋₄ alkylene-C₃₋₈cycloalkyl. In some embodiments, R¹¹ is optionally substituted —C₁₋₄alkylene-C₂₋₇ heterocycloalkyl. In some embodiments, R¹¹ is optionallysubstituted —C₁₋₄ alkylene-phenyl. In some embodiments, R¹¹ isoptionally substituted —C₁₋₄ alkylene-heteroaryl.

In some embodiments of Formula (VI), each of R¹² is independentlyselected from hydrogen, halogen, —OH, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, and C₃₋₆ carbocycle, 3-to 6-membered heterocycle, wherein the C₃₋₆ carbocycle and 3- to6-membered heterocycle is optionally substituted with one or moresubstituents independently selected from halogen, —OH, oxo, amino, —NO₂,—CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl. In some embodiments ofFormula (VI), each of R¹² is independently selected from hydrogen, —NO₂,—CN, C₁₋₆ alkyl, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, andC₃₋₆ carbocycle, 3- to 6-membered heterocycle, wherein the C₃₋₆carbocycle and 3- to 6-membered heterocycle is optionally substitutedwith one or more substituents independently selected from halogen, —OH,oxo, amino, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl. Insome embodiments, R¹² is hydrogen. In some embodiments, R¹² is halogen.In some embodiments, R¹² is —OH. In some embodiments, R¹² is —NO₂. Insome embodiments, R¹² is —CN. In some embodiments, R¹² is C₁₋₆ alkyl. Insome embodiments, R¹² is C₁₋₆ aminoalkyl. In some embodiments, R¹² isC₁₋₆ hydroxyalkyl. In some embodiments, R¹² is C₁₋₆ haloalkyl. In someembodiments, R¹² is and C₃₋₆ carbocycle. In some embodiments, R¹² is 3-to 6-membered heterocycle, wherein the C₃₋₆ carbocycle and 3- to6-membered heterocycle is optionally substituted with one or moresubstituents independently selected from halogen, —OH, oxo, amino, —NO₂,—CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl. In some embodiments,the one or more substituent is halogen. In some embodiments, the one ormore substituent is —OH. In some embodiments, the one or moresubstituent is oxo. In some embodiments, the one or more substituent isamino. In some embodiments, the one or more substituent is —NO₂. In someembodiments, the one or more substituent is —CN. In some embodiments,the one or more substituent is C₁₋₆ alkyl. In some embodiments, the oneor more substituent is C₁₋₆ alkoxy. In some embodiments, the one or moresubstituent is C₁₋₆ haloalkyl.

In some embodiments of Formula (VI), R^(B) is hydrogen, halo, —CN, —NO₂,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₁₋₆heteroalkyl, —OR¹¹, —SR¹¹, —N(R¹²)(R¹¹), —C(O)R¹², —C(O)OR¹², —OC(O)R¹²,—OC(O)N(R¹²)(R¹¹), —C(O)N(R¹²)(R¹¹), —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,—N(R¹²)C(O)N(R¹²)(R¹¹), —N(R¹²)S(O)₂(R¹²), —S(O)R¹², —S(O)₂R¹²,—S(O)₂N(R¹²)(R¹¹), optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₂₋₉ heterocycloalkyl, optionally substituted naphthyl,optionally substituted phenyl, optionally substituted monocyclicheteroaryl, or optionally substituted bicyclic heteroaryl. In someembodiments, R^(B) is hydrogen. In some embodiments, R^(B) is halo. Insome embodiments, R^(B) is —CN. In some embodiments, R^(B) is —NO₂. Insome embodiments, R^(B) is optionally substituted C₁₋₆ alkyl. In someembodiments, R^(B) is optionally substituted C₂₋₆ alkenyl. In someembodiments, R^(B) is optionally substituted C₂₋₆ alkynyl. In someembodiments, R^(B) is optionally substituted C₁₋₆ heteroalkyl. In someembodiments, R^(B) is —OR¹¹. In some embodiments, R^(B) is —SR¹¹. Insome embodiments, R^(B) is —N(R¹²)(R¹¹). In some embodiments, R^(B) is—C(O)R¹². In some embodiments, R^(B) is —C(O)OR¹². In some embodiments,R^(B) is —OC(O)R¹². In some embodiments, R^(B) is —OC(O)N(R¹²)(R¹¹). Insome embodiments, R^(B) is —C(O)N(R¹²)(R¹¹). In some embodiments, R^(B)is —N(R¹²)C(O)R¹². In some embodiments, R^(B) is —N(R¹²)C(O)OR¹². Insome embodiments, R^(B) is —N(R¹²)C(O)N(R²)(R¹¹). In some embodiments,R^(B) is —N(R¹²)S(O)₂(R¹²). In some embodiments, R^(B) is —S(O)R¹². Insome embodiments, R^(B) is —S(O)₂R¹². In some embodiments, R^(B) is—S(O)₂N(R¹²)(R¹¹). In some embodiments, R^(B) is optionally substitutedC₃₋₈ cycloalkyl. In some embodiments, R^(B) is optionally substitutedC₂₋₉ heterocycloalkyl. In some embodiments, R^(B) is optionallysubstituted naphthyl. In some embodiments, R^(B) is optionallysubstituted phenyl. In some embodiments, R^(B) is optionally substitutedmonocyclic heteroaryl. In some embodiments, R^(B) is optionallysubstituted bicyclic heteroaryl.

In some embodiments of Formula (VI), m is 1, 2, 3, or 4. In someembodiments, m is 1. In some embodiments, m is 2. In some embodiments, mis 3. In some embodiments, m is 4.

In some embodiments of Formula (VI), p is 0 or 1. In some embodiments, pis 0. In some embodiments, p is 1.

Non-limiting examples of compounds described herein, are compoundspresented in Table 1, and pharmaceutically acceptable salts or solvatesthereof.

TABLE 1 Exemplary Compounds of the Disclosure Ex- ample No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

Table 2 presents corresponding biological data for USP1 IC50 (nM) andMDA-MB-436 IC50 (nM) for the compounds presented in Table 1.

TABLE 2 Example USP1 IC₅₀ MDA-MB-436 No. (nM) IC₅₀ (nM)  1 A A  2 B B  3A A  4 A A  5 A A  6 A A  7 A A  8 A A  9 A A 10 A A 11 A A 13 B B 15 AB 16 B B 17 A A 18 A A 20 B B 21 C — 24 A B 25 A A 26 B B 27 A A 28 A A29 B B 30 A A 31 A B 32 A B

IC₅₀ (nM): 0<A≤50; 50<B≤1,000; 1,000<C≤10,000

Included in the present disclosure are salts, particularlypharmaceutically acceptable salts, of the compounds described herein.The compounds of the present disclosure that possess a sufficientlyacidic, a sufficiently basic, or both functional groups, can react withany of a number of inorganic bases, and inorganic and organic acids, toform a salt. Alternatively, compounds that are inherently charged, suchas those with a quaternary nitrogen, can form a salt with an appropriatecounterion, e.g., a halide such as bromide, chloride, or fluoride,particularly bromide.

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds can exist in Z- or E-form (or cis- or trans-form).Furthermore, some chemical entities can exist in various tautomericforms. Unless otherwise specified, compounds described herein areintended to include all Z-, E- and tautomeric forms as well.

As used herein, “phenyl isostere” refers to a moiety or a functionalgroup that exhibits similar physical, biological and/or chemicalproperties as a phenyl group. Exemplary phenyl isosteres include,without limitation, cubane, bicyclo[1.1.1]pentane (BCP),bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane,adamantane, norbornene, closo-1,2-carborane, closo-1,7-carborane,closo-1,12-carborane, and ethynyl group. In some embodiments, the phenylisostere is cubane. In some embodiments, the phenyl isostere is anethynyl group.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

The compounds disclosed herein, in some embodiments, are used indifferent enriched isotopic forms, e.g., enriched in the content of ²H,³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound isdeuterated in at least one position. Such deuterated forms can be madeby the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Asdescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration canimprove the metabolic stability and or efficacy, thus increasing theduration of action of drugs.

Unless otherwise stated, compounds described herein may exhibit theirnatural isotopic abundance, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areencompassed within the scope of the present disclosure. For example, thecompounds described herein may be artificially enriched in one or moreparticular isotopes. In some embodiments, the compounds described hereinmay be artificially enriched in one or more isotopes that are notpredominantly found in nature. In some embodiments, the compoundsdescribed herein may be artificially enriched in one or more isotopesselected from deuterium (2H), tritium (3H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). In some embodiments, the compounds described herein areartificially enriched in one or more isotopes selected from ²H, ¹¹C,¹³C, 14C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F,³³, ³⁴, ³⁵S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹³¹I, and ¹²⁵I. In someembodiments, the abundance of the enriched isotopes is independently atleast 1%, at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80%, at least 90%, or100% by molar.

In some embodiments of a compound disclosed herein, one or more of R¹,R⁴, R^(4′), R⁵, R^(5′), R⁶, R^(6′), R⁸, R⁹, R^(Y1), R^(Y2), R^(Y3),R^(Y4), R¹¹, R¹², R^(A), R^(B), R^(B1), R^(1Ca), R^(1Da), R^(a), R^(b),R^(c), and/or R^(d) groups comprise deuterium at a percentage higherthan the natural abundance of deuterium.

In some embodiments of a compound disclosed herein, one or more ¹H arereplaced with one or more deuteriums in one or more of the followinggroups R¹, R⁴, R^(4′), R⁵, R^(5′), R⁶, R^(6′), R⁸, R⁹, R^(Y1), R^(Y2),R^(Y3), R^(Y4), R¹¹, R¹², R^(A), R^(B), R^(B1), R^(1Ca), R^(1Da), R^(a),R^(b), R^(c), and/or R^(d).

In some embodiments of a compound disclosed herein, the abundance ofdeuterium in each of R¹, R⁴, R^(4′), R⁵, R^(5′), R⁶, R^(6′), R⁸, R⁹,R^(Y1), R^(Y2), R³, R⁴, R¹¹, R¹², R^(A), R^(B), R^(B1), R^(1Ca),R^(1Da), R^(a), R^(b), R^(c), and/or R^(d) is independently at least 1%,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

In some embodiments of a compound disclosed herein, one or more ¹H ofRing A, Ring C, and/or Ring D are replaced with one or more deuteriums.

In certain embodiments, the compounds disclosed herein have some or allof the ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing compounds are known in the art and include, by wayof non-limiting example only, the following synthetic methods. Deuteriumsubstituted compounds can be synthesized using various methods such asdescribed in: Dean, Dennis C.; Editor. Recent Advances in the Synthesisand Applications of Radiolabeled Compounds for Drug Discovery andDevelopment. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; GeorgeW.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds viaOrganometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; andEvans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal.Chem., 1981, 64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing compounds. Large numbers of deuterium-containingreagents and building blocks are available commercially from chemicalvendors, such as Aldrich Chemical Co.

Compounds of the present disclosure also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof.

The compounds described herein can in some cases exist as diastereomers,enantiomers, or other stereoisomeric forms. Where absolutestereochemistry is not specified, the compounds presented herein includeall diastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Separation of stereoisomers can beperformed by chromatography or by forming diastereomers and separatingby recrystallization, or chromatography, or any combination thereof.(Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racematesand Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporatedby reference for this disclosure). Stereoisomers can also be obtained bystereoselective synthesis.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein can be in the form of pharmaceuticallyacceptable salts. As well, in some embodiments, active metabolites ofthese compounds having the same type of activity are included in thescope of the present disclosure. In addition, the compounds describedherein can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein.

In certain embodiments, compounds or salts of the compounds can beprodrugs, e.g., wherein a hydroxyl in the parent compound is presentedas an ester or a carbonate, or carboxylic acid present in the parentcompound is presented as an ester. The term “prodrug” is intended toencompass compounds which, under physiologic conditions, are convertedinto pharmaceutical agents of the present disclosure. One method formaking a prodrug is to include one or more selected moieties which arehydrolyzed under physiologic conditions to reveal the desired molecule.In other embodiments, the prodrug is converted by an enzymatic activityof the host animal such as specific target cells in the host animal. Forexample, esters or carbonates (e.g., esters or carbonates of alcohols orcarboxylic acids and esters of phosphonic acids) are preferred prodrugsof the present disclosure.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds can be a prodrug for another derivative oractive compound.

Prodrugs are often useful because, in some situations, they can beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Prodrugscan help enhance the cell permeability of a compound relative to theparent drug. The prodrug can also have improved solubility inpharmaceutical compositions over the parent drug. Prodrugs can bedesigned as reversible drug derivatives, for use as modifiers to enhancedrug transport to site-specific tissues or to increase drug residenceinside of a cell.

In some embodiments, the design of a prodrug increases the lipophilicityof the pharmaceutical agent. In some embodiments, the design of aprodrug increases the effective water solubility. See, e.g., Fedorak etal., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein for such disclosure). According to another embodiment, thepresent disclosure provides methods of producing the above-definedcompounds. The compounds can be synthesized using conventionaltechniques. Advantageously, these compounds are conveniently synthesizedfrom readily available starting materials.

Synthetic chemistry transformations and methodologies useful insynthesizing the compounds described herein are known in the art andinclude, for example, those described in R. Larock, ComprehensiveOrganic Transformations (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

C. Pharmaceutical Compositions

Provided herein, in certain embodiments, are compositions comprising atherapeutically effective amount of any compound or salt of any one ofFormulas (IVa), (IVa-1), (IVa-2), and (VI) (also referred to herein as“a pharmaceutical agent”).

Pharmaceutical compositions can be formulated using one or morephysiologically acceptable carriers including excipients and auxiliarieswhich facilitate processing of the pharmaceutical agent intopreparations which are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions is found, for example, in Remington: TheScience and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins, 1999).

The compositions and methods of the present disclosure can be utilizedto treat an individual in need thereof. In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thepharmaceutical agent, is preferably administered as a pharmaceuticalcomposition comprising, for example, a pharmaceutical agent and apharmaceutically acceptable carrier or excipient. Pharmaceuticallyacceptable carriers are well known in the art and include, for example,aqueous solutions such as water or physiologically buffered saline orother solvents or vehicles such as glycols, glycerol, oils such as oliveoil, or injectable organic esters. In a preferred embodiment, when suchpharmaceutical compositions are for human administration, particularlyfor invasive routes of administration, e.g., routes, such as injectionor implantation, that circumvent transport or diffusion through anepithelial barrier, the aqueous solution is pyrogen-free, orsubstantially pyrogen-free. The excipients can be chosen, for example,to effect delayed release of an agent or to selectively target one ormore cells, tissues or organs. The pharmaceutical composition can be indosage unit form such as tablet, capsule, granule, lyophile forreconstitution, powder, solution, syrup, suppository, injection or thelike. The composition can also be present in a transdermal deliverysystem, e.g., a skin patch. The composition can also be present in asolution suitable for topical administration, such as an eye drop.

A pharmaceutically acceptable excipient can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as apharmaceutical agent. Such physiologically acceptable agents include,for example, carbohydrates, such as glucose, sucrose or dextrans,antioxidants, such as ascorbic acid or glutathione, chelating agents,low molecular weight proteins or other stabilizers or excipients. Thechoice of a pharmaceutically acceptable excipient, including aphysiologically acceptable agent, depends, for example, on the route ofadministration of the composition. The preparation or pharmaceuticalcomposition can be a self-emulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition(preparation) also can be a liposome or other polymer matrix, which canhave incorporated therein, for example, a compound of the disclosure.Liposomes, for example, which comprise phospholipids or other lipids,are nontoxic, physiologically acceptable and metabolizable carriers thatare relatively simple to make and administer.

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally, for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules, including sprinkle capsulesand gelatin capsules, boluses, powders, granules, pastes for applicationto the tongue; absorption through the oral mucosa, e.g., sublingually;anally, rectally or vaginally, for example, as a pessary, cream or foam;parenterally, including intramuscularly, intravenously, subcutaneouslyor intrathecally as, for example, a sterile solution or suspension;nasally; intraperitoneally; subcutaneously; transdermally, for example,as a patch applied to the skin; and topically, for example, as a cream,ointment or spray applied to the skin, or as an eye drop. The compoundcan also be formulated for inhalation. In certain embodiments, acompound can be simply dissolved or suspended in sterile water.

A pharmaceutical composition can be a sterile aqueous or non-aqueoussolution, suspension or emulsion, e.g., a microemulsion. The excipientsdescribed herein are examples and are in no way limiting. An effectiveamount or therapeutically effective amount refers to an amount of theone or more pharmaceutical agents administered to a subject, either as asingle dose or as part of a series of doses, which is effective toproduce a desired therapeutic effect.

Subjects can generally be monitored for therapeutic effectiveness usingassays and methods suitable for the condition being treated, whichassays will be familiar to those having ordinary skill in the art andare described herein. Pharmacokinetics of a pharmaceutical agent, or oneor more metabolites thereof, that is administered to a subject can bemonitored by determining the level of the pharmaceutical agent ormetabolite in a biological fluid, for example, in the blood, bloodfraction, e.g., serum, and/or in the urine, and/or other biologicalsample or biological tissue from the subject. Any method practiced inthe art and described herein to detect the agent can be used to measurethe level of the pharmaceutical agent or metabolite during a treatmentcourse.

The dose of a pharmaceutical agent described herein for treating adisease or disorder can depend upon the subject's condition, that is,stage of the disease, severity of symptoms caused by the disease,general health status, as well as age, gender, and weight, and otherfactors apparent to a person skilled in the medical art. Pharmaceuticalcompositions can be administered in a manner appropriate to the diseaseto be treated as determined by persons skilled in the medical arts. Inaddition to the factors described herein and above related to use ofpharmaceutical agent for treating a disease or disorder, suitableduration and frequency of administration of the pharmaceutical agent canalso be determined or adjusted by such factors as the condition of thepatient, the type and severity of the patient's disease, the particularform of the active ingredient, and the method of administration. Optimaldoses of an agent can generally be determined using experimental modelsand/or clinical trials. The optimal dose can depend upon the body mass,weight, or blood volume of the subject. The use of the minimum dose thatis sufficient to provide effective therapy is usually preferred. Designand execution of pre-clinical and clinical studies for a pharmaceuticalagent, including when administered for prophylactic benefit, describedherein are well within the skill of a person skilled in the relevantart. When two or more pharmaceutical agents are administered to treat adisease or disorder, the optimal dose of each pharmaceutical agent canbe different, such as less than when either agent is administered aloneas a single agent therapy. In certain particular embodiments, twopharmaceutical agents in combination can act synergistically oradditively, and either agent can be used in a lesser amount than ifadministered alone. An amount of a pharmaceutical agent that can beadministered per day can be, for example, between about 0.01 mg/kg and100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg bodyweight. In other embodiments, the amount of a pharmaceutical agent thatcan be administered per day is between about 0.01 mg/kg and 1000 mg/kg,between about 100-500 mg/kg, or between about 500-1000 mg/kg bodyweight. The optimal dose, per day or per course of treatment, can bedifferent for the disease or disorder to be treated and can also varywith the administrative route and therapeutic regimen.

Pharmaceutical compositions comprising a pharmaceutical agent can beformulated in a manner appropriate for the delivery method by usingtechniques routinely practiced in the art.

The composition can be in the form of a solid, e.g., tablet, capsule,semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In otherembodiments, the pharmaceutical composition is administered as a bolusinfusion.

Pharmaceutical acceptable excipients are well known in thepharmaceutical art and described, for example, in Rowe et al., Handbookof Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties,and Safety, 5^(th) Ed., 2006, and in Remington: The Science and Practiceof Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).Exemplary pharmaceutically acceptable excipients include sterile salineand phosphate buffered saline at physiological pH. Preservatives,stabilizers, dyes, buffers, and the like can be provided in thepharmaceutical composition. In addition, antioxidants and suspendingagents can also be used. In general, the type of excipient is selectedbased on the mode of administration, as well as the chemical compositionof the active ingredient(s). Alternatively, compositions describedherein can be formulated as a lyophilizate. A composition describedherein can be lyophilized or otherwise formulated as a lyophilizedproduct using one or more appropriate excipient solutions forsolubilizing and/or diluting the pharmaceutical agent(s) of thecomposition upon administration. In other embodiments, thepharmaceutical agent can be encapsulated within liposomes usingtechnology known and practiced in the art. In certain particularembodiments, a pharmaceutical agent is not formulated within liposomesfor application to a stent that is used for treating highly, though nottotally, occluded arteries. Pharmaceutical compositions can beformulated for any appropriate manner of administration described hereinand, in the art.

A pharmaceutical composition, e.g., for oral administration or forinjection, infusion, subcutaneous delivery, intramuscular delivery,intraperitoneal delivery or other method, can be in the form of aliquid. A liquid pharmaceutical composition can include, for example,one or more of the following: a sterile diluent such as water, salinesolution, preferably physiological saline, Ringer's solution, isotonicsodium chloride, fixed oils that can serve as the solvent or suspendingmedium, polyethylene glycols, glycerin, propylene glycol or othersolvents; antibacterial agents; antioxidants; chelating agents; buffersand agents for the adjustment of tonicity such as sodium chloride ordextrose. A parenteral composition can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic. Theuse of physiological saline is preferred, and an injectablepharmaceutical composition is preferably sterile. In another embodiment,for treatment of an ophthalmological condition or disease, a liquidpharmaceutical composition can be applied to the eye in the form of eyedrops. A liquid pharmaceutical composition can be delivered orally.

For oral formulations, at least one of the pharmaceutical agentsdescribed herein can be used alone or in combination with appropriateadditives to make tablets, powders, granules or capsules, and ifdesired, with diluents, buffering agents, moistening agents,preservatives, coloring agents, and flavoring agents. The pharmaceuticalagents can be formulated with a buffering agent to provide forprotection of the compound from low pH of the gastric environment and/oran enteric coating. A pharmaceutical agent included in a pharmaceuticalcomposition can be formulated for oral delivery with a flavoring agent,e.g., in a liquid, solid or semi-solid formulation and/or with anenteric coating.

A pharmaceutical composition comprising any one of the pharmaceuticalagents described herein can be formulated for sustained or slow release,also called timed release or controlled release. Such compositions cangenerally be prepared using well known technology and administered by,for example, oral, rectal, intradermal, or subcutaneous implantation, orby implantation at the desired target site. Sustained-releaseformulations can contain the compound dispersed in a carrier matrixand/or contained within a reservoir surrounded by a rate controllingmembrane. Excipients for use within such formulations are biocompatible,and can also be biodegradable; preferably the formulation provides arelatively constant level of active component release. The amount ofpharmaceutical agent contained within a sustained release formulationdepends upon the site of implantation, the rate and expected duration ofrelease, and the nature of the condition, disease or disorder to betreated or prevented.

In certain embodiments, the pharmaceutical compositions comprising apharmaceutical agent are formulated for transdermal, intradermal, ortopical administration. The compositions can be administered using asyringe, bandage, transdermal patch, insert, or syringe-like applicator,as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam,cream, gel, paste. This preferably is in the form of a controlledrelease formulation or sustained release formulation administeredtopically or injected directly into the skin adjacent to or within thearea to be treated, e.g., intradermally or subcutaneously. The activecompositions can also be delivered via iontophoresis. Preservatives canbe used to prevent the growth of fungi and other microorganisms.Suitable preservatives include, but are not limited to, benzoic acid,butylparaben, ethyl paraben, methyl paraben, propylparaben, sodiumbenzoate, sodium propionate, benzalkonium chloride, benzethoniumchloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol,phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

Pharmaceutical compositions comprising a pharmaceutical agent can beformulated as emulsions for topical application. An emulsion containsone liquid distributed in the body of a second liquid. The emulsion canbe an oil-in-water emulsion or a water-in-oil emulsion. Either or bothof the oil phase and the aqueous phase can contain one or moresurfactants, emulsifiers, emulsion stabilizers, buffers, and otherexcipients. The oil phase can contain other oily pharmaceuticallyapproved excipients. Suitable surfactants include, but are not limitedto, anionic surfactants, non-ionic surfactants, cationic surfactants,and amphoteric surfactants. Compositions for topical application canalso include at least one suitable suspending agent, antioxidant,chelating agent, emollient, or humectant.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions can be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. Liquid sprays can be delivered from pressurized packs,for example, via a specially shaped closure. Oil-in-water emulsions canalso be used in the compositions, patches, bandages and articles. Thesesystems are semisolid emulsions, micro-emulsions, or foam emulsionsystems.

In some embodiments, the pharmaceutical agent described herein can beformulated as in inhalant. Inhaled methods can deliver medicationdirectly to the airway. The pharmaceutical agent can be formulated asaerosols, microspheres, liposomes, or nanoparticles. The pharmaceuticalagent can be formulated with solvents, gases, nitrates, or anycombinations thereof. Compositions described herein are optionallyformulated for delivery as a liquid aerosol or inhalable dry powder.Liquid aerosol formulations are optionally nebulized predominantly intoparticle sizes that can be delivered to the terminal and respiratorybronchioles. Liquid aerosol and inhalable dry powder formulations arepreferably delivered throughout the endobronchial tree to the terminalbronchioles and eventually to the parenchymal tissue.

Aerosolized formulations described herein are optionally delivered usingan aerosol forming device, such as a jet, vibrating porous plate orultrasonic nebulizer, preferably selected to allow the formation ofaerosol particles having with a mass medium average diameterpredominantly between 1 to 5μ. Further, the formulation preferably hasbalanced osmolarity ionic strength and chloride concentration, and thesmallest aerosolizable volume able to deliver effective dose of thepharmaceutical agent. Additionally, the aerosolized formulationpreferably does not impair negatively the functionality of the airwaysand does not cause undesirable side effects.

Aerosolization devices suitable for administration of aerosolformulations described herein include, for example, jet, vibratingporous plate, ultrasonic nebulizers and energized dry powder inhalers,that are able to nebulize the formulation into aerosol particle sizepredominantly in the size range from 1-5μ. Predominantly in thisapplication means that at least 70% but preferably more than 90% of allgenerated aerosol particles are within 1-5μ range. A jet nebulizer worksby air pressure to break a liquid solution into aerosol droplets.Vibrating porous plate nebulizers work by using a sonic vacuum producedby a rapidly vibrating porous plate to extrude a solvent droplet througha porous plate. An ultrasonic nebulizer works by a piezoelectric crystalthat shears a liquid into small aerosol droplets. A variety of suitabledevices are available, including, for example, AeroNeb™ and AeroDose™vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, Calif.),Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC®and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc.,Ruchmond, Va.), and Aerosonic™ (DeVilbiss Medizinische Produkte(Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare,Inc., Vernon Hills, Ill.) ultrasonic nebulizers.

In some embodiments, the pharmaceutical agent(s) can be formulated witholeaginous bases or ointments to form a semisolid composition with adesired shape. In addition to the pharmaceutical agent, these semisolidcompositions can contain dissolved and/or suspended bactericidal agents,preservatives and/or a buffer system. A petrolatum component that can beincluded can be any paraffin ranging in viscosity from mineral oil thatincorporates isobutylene, colloidal silica, or stearate salts toparaffin waxes. Absorption bases can be used with an oleaginous system.Additives can include cholesterol, lanolin (lanolin derivatives,beeswax, fatty alcohols, wool wax alcohols, low HLB(hydrophobellipophobe balance) emulsifiers, and assorted ionic andnonionic surfactants, singularly or in combination.

Controlled or sustained release transdermal or topical formulations canbe achieved by the addition of time-release additives, such as polymericstructures, matrices, that are available in the art. For example, thecompositions can be administered through use of hot-melt extrusionarticles, such as bioadhesive hot-melt extruded film. The formulationcan comprise a cross-linked polycarboxylic acid polymer formulation. Across-linking agent can be present in an amount that provides adequateadhesion to allow the system to remain attached to target epithelial orendothelial cell surfaces for a sufficient time to allow the desiredrelease of the compound.

An insert, transdermal patch, bandage or article can comprise a mixtureor coating of polymers that provide release of the pharmaceutical agentsat a constant rate over a prolonged period of time. In some embodiments,the article, transdermal patch or insert comprises water-soluble poreforming agents, such as polyethylene glycol (PEG) that can be mixed withwater insoluble polymers to increase the durability of the insert and toprolong the release of the active ingredients.

Transdermal devices (inserts, patches, bandages) can also comprise awater insoluble polymer. Rate controlling polymers can be useful foradministration to sites where pH change can be used to effect release.These rate controlling polymers can be applied using a continuouscoating film during the process of spraying and drying with the activecompound. In one embodiment, the coating formulation is used to coatpellets comprising the active ingredients that are compressed to form asolid, biodegradable insert.

A polymer formulation can also be utilized to provide controlled orsustained release. Bioadhesive polymers described in the art can beused. By way of example, a sustained-release gel and the compound can beincorporated in a polymeric matrix, such as a hydrophobic polymermatrix. Examples of a polymeric matrix include a microparticle. Themicroparticles can be microspheres, and the core can be of a differentmaterial than the polymeric shell. Alternatively, the polymer can becast as a thin slab or film, a powder produced by grinding or otherstandard techniques, or a gel such as a hydrogel. The polymer can alsobe in the form of a coating or part of a bandage, stent, catheter,vascular graft, or other device to facilitate delivery of thepharmaceutical agent. The matrices can be formed by solvent evaporation,spray drying, solvent extraction and other methods known to thoseskilled in the art.

Kits with unit doses of one or more of the agents described herein,usually in oral or injectable doses, are provided. Such kits can includea container containing the unit dose, an informational package insertdescribing the use and attendant benefits of the drugs in treatingdisease, and optionally an appliance or device for delivery of thecomposition.

D. Methods of Treatment

Ubiquitin Specific Protease 1 (USP1) is a member of theubiquitin-specific processing family of proteases. USP1 is adeubiquitinating enzyme (“DUB”) and deubiquitinates its substratesinvolved in key oncogenic pathways to modulate their functions. Amongits roles, USP1 can exhibit DNA-mediated activation at the replicationfork, protects the fork, and promote survival in BRCA1-deficient cells.As loss of both USP1 and BRCA1 leads to replication fork degradation,inhibition of USP1 can selectively decrease the viability, or kill,tumor cells with defects in BRCA defects without affecting the survivalof cells with normal BRCA function.

In the United States (US), it has been estimated that inherited BRCA1and BRCA2 mutations are present in 5-10% of breast cancers and 10-15% ofovarian cancers. Breast cancer is the most common cancer in the worldand the most common malignancy in women. BRCA1 and BRCA2 can be detectedin at least 5% of unselected breast cancer patients and in approximately30% of patients with a family history of developing breast or ovariancancer. At present, treatment options including chemotherapy and immunecheckpoint inhibitors are limited for breast cancer patients withgermline BRCA mutations, more aggressive progression and higher risk ofrecurrence. While PARP inhibitors have been approved by the US Food andDrug Administration (FDA) as monotherapies for deleterious/suspecteddeleterious germline BRCA-mutated, HER2-negative breast cancer, in somecases, resistance to the PARP inhibitors can be observed to developquickly in breast cancer patients. Ovarian cancers represent aheterogenous group of solid tumors. On average, one in five ovariancancer can be associated with germline mutations. Of those ovariancancers with germline mutations, 65-85% can be associated with germlineBRCA mutations. Similar to the breast cancer setting, while the PARPinhibitors can be the first-line maintenance therapy for patients withBRCA-mutated ovarian cancer, those patients can develop resistance tothe PARP inhibitors.

The compounds described herein can be used as inhibitors of USP1. Suchcompounds can exhibit BRCA1 and/or BRCA2 mutant-selective,anti-proliferative activities. The compounds described herein can beused to treat BRCA1 and/or BRCA2 mutant or homologous recombination(HRD) positive cancers. The compounds described herein can exhibitanti-proliferative activities in cancer cells with a BRCA1 and/or BRCA2mutation, particularly MDA-MB-436 cells. The compounds described hereinmay not exhibit similar anti-proliferative activities in cancer cellswith wild-type BRCA, particularly SNG-M cells. In some embodiments, thecompounds described herein can show selectivity for mutant BRCA1 and/orBRCA2 over wild-type BRCA of at least 50-fold, 100-fold, 150-fold,200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold,550-fold, 600-fold, or more.

The compounds described herein can be used in the preparation ofmedicaments for the prevention or treatment of diseases or conditions.In some embodiments, the compounds described herein are used in a methodof modulating USP1 in a subject. In some embodiments, the compoundsdescribed herein are used in a method of inhibiting USP1 in subject. Insome embodiments, the compounds described herein are used in a method ofinhibiting or reducing DNA repair activity modulated by USP1 in asubject. In some embodiments, the compounds herein are used in a methodof treating a disease or disorder associated with USP1 in a subject. Insome embodiments, the compounds described herein are used in a method oftreating a disease or disorder associated with modulation of USP in asubject. In addition, a method for modulating, inhibiting, or treatingany of the diseases or conditions described herein in a subject in needof such treatment, involves administration of pharmaceuticalcompositions containing at least one compound described herein, or apharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, response to the drugs, and the judgment of thetreating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity, course of the disease,disorder or condition, previous therapy, the patient's health status andresponse to the drugs, and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds can beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.02-about 5000 mg per day, in some embodiments, about 1-about1500 mg per day. The desired dose can conveniently be presented in asingle dose or as divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day.

The pharmaceutical composition described herein can be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage can bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-recloseable containers. Alternatively,multiple-dose recloseable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection can be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage can vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

In one aspect, the disclosure provides a method of modulating USP1 in asubject, comprising administering to the subject a compound describedherein, or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the disclosure provides a method of inhibiting USP1 in asubject, comprising administering to the subject a compound describedherein, or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the disclosure provides a method of inhibiting orreducing DNA repair activity modulated by USP1 in a subject in needthereof, the method comprising administering a therapeutically effectiveamount of a compound described herein, or a pharmaceutically acceptablesalt or solvate thereof, or a pharmaceutical composition describedherein.

In one aspect, the disclosure provides a method of treating a disease ordisorder associated with USP1 in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound described herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition of described herein. Insome embodiments, the disease or a disorder is cancer.

In one aspect, the disclosure provides a method of treating a disease ordisorder associated with modulation of USP1 in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound described herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition of described herein. Insome embodiments, the disease or disorder is cancer.

In one aspect, the disclosure provides a method of treating cancer in asubject, comprising administering to the subject in need thereof aneffective amount of a compound described herein, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition ofdescribed herein.

In some embodiments, administration of a compound described herein, or apharmaceutically acceptable salt or solvate thereof can further comprisecombination with other biologically active ingredients (e.g., a secondtherapeutic agent). Other biologically active ingredients can include asecond and different antineoplastic agent or a second agent that targetsa USP1 independent mechanism of DNA repair. In some embodiments,administration of a compound described herein, or a pharmaceuticallyacceptable salt or solvate thereof can further comprise combination witha non-drug therapy. Non-drug therapy can include surgery, radiationtreatment, or any other type of therapy which does not includeadministering a drug. Such combination of the compounds describedherein, or pharmaceutically acceptable salts or solvates thereof, withother biological active ingredients or non-drug therapies can enhancethe effect of the compounds described herein, or pharmaceuticallyacceptable salts or solvates thereof. The compounds described herein canbe administered simultaneously or sequentially to other biologicalactive ingredients, but at least two or more compounds or biologicallyactive ingredients can be administered during a single cycle or courseof therapy. In some embodiments, the second therapeutic agent is a polyADP-ribose polymerase (PARP) inhibitor. In some embodiments, a USP1inhibitor described herein is administered with two PARP inhibitors. Insome embodiments, the PARP inhibitor is olaparib, niraparib,talazoparib, or rucaparib.

In one aspect, the disclosure provides a method of treating cancer in asubject, comprising administering to the subject in need thereof anamount of a compound described herein, or a pharmaceutically acceptablesalt or solvate thereof, or a pharmaceutical composition of describedherein. In some embodiments, the cancer is leukemia, acute myeloidleukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia(ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiplemyeloma (MM).

In some embodiments, the cancer is a carcinoma, squamous carcinoma,adenocarcinoma, sarcomata, endometrial cancer, breast cancer, ovariancancer, cervical cancer, fallopian tube cancer, primary peritonealcancer, colon cancer, colorectal cancer, squamous cell carcinoma of theanogenital region, melanoma, renal cell carcinoma, lung cancer,non-small cell lung cancer, squamous cell carcinoma of the lung, stomachcancer, bladder cancer, gall bladder cancer, liver cancer, thyroidcancer, laryngeal cancer, salivary gland cancer, esophageal cancer, headand neck cancer, glioblastoma, glioma, squamous cell carcinoma of thehead and neck, prostate cancer, pancreatic cancer, mesothelioma,sarcoma, hematological cancer, leukemia, lymphoma, neuroma, andcombinations thereof. In some embodiments, a cancer to be treated by themethods of the present disclosure include, for example, carcinoma,squamous carcinoma (for example, cervical canal, eyelid, tunicaconjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue,larynx, and gullet), and adenocarcinoma (for example, prostate, smallintestine, endometrium, cervical canal, large intestine, lung, pancreas,gullet, rectum, uterus, stomach, mammary gland, and ovary). In someembodiments, a cancer to be treated by the methods of the presentdisclosure further include sarcomata (for example, myogenic sarcoma),leukosis, neuroma, melanoma, and lymphoma. In some embodiments, a cancerto be treated by the methods of the present disclosure is breast cancer.In some embodiments, a cancer to be treated by the methods of treatmentof the present disclosure is triple negative breast cancer (TNBC). Insome embodiments, a cancer to be treated by the methods of treatment ofthe present disclosure is ovarian cancer. In some embodiments, a cancerto be treated by the methods of treatment of the present disclosure iscolorectal cancer. In some embodiments, the cancer is ahomolgous-recombination deficient cancer. In some embodiments, thecancer comprises cancer cells with a mutation in a gene encoding p53.

In some embodiments, a patient or population of patients to be treatedwith a pharmaceutical composition of the present disclosure have a solidtumor. In some embodiments, a solid tumor is a melanoma, renal cellcarcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer,colon cancer, gall bladder cancer, laryngeal cancer, liver cancer,thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer,pancreatic cancer, or Merkel cell carcinoma. In some embodiments, apatient or population of patients to be treated with a pharmaceuticalcomposition of the present disclosure have a hematological cancer. Insome embodiments, the patient has a hematological cancer such as Diffuselarge B cell lymphoma (“DLBCL”), Hodgkin's lymphoma (“HL”),Non-Hodgkin's lymphoma (“NHL”), Follicular lymphoma (“FL”), acutemyeloid leukemia (“AML”), or Multiple myeloma (“MM”). In someembodiments, a patient or population of patients to be treated havingthe cancer selected from the group consisting of ovarian cancer, lungcancer and melanoma.

Specific examples of cancers that can be prevented and/or treated inaccordance with present disclosure include, but are not limited to, thefollowing: renal cancer, kidney cancer, glioblastoma multiforme,metastatic breast cancer; breast carcinoma; breast sarcoma;neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma;malignant melanoma; carcinomas of the epidermis; leukemias such as butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplasticsyndrome, chronic leukemias such as but not limited to, chronicmyelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairycell leukemia; polycythemia vera; lymphomas such as but not limited toHodgkin's disease, non-Hodgkin's disease; multiple myelomas such as butnot limited to smoldering multiple myeloma, nonsecretory myeloma,osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma andextramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonalgammopathy of undetermined significance; benign monoclonal gammopathy;heavy chain disease; bone cancer and connective tissue sarcomas such asbut not limited to bone sarcoma, myeloma bone disease, multiple myeloma,cholesteatoma-induced bone osteosarcoma, Paget's disease of bone,osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant celltumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangio sarcoma, neurilemmoma,rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but notlimited to, glioma, astrocytoma, brain stem glioma, ependymoma,oligodendroglioma, nonglial tumor, acoustic neurinoma,craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; breast cancer including butnot limited to adenocarcinoma, lobular (small cell) carcinoma,intraductal carcinoma, medullary breast cancer, mucinous breast cancer,tubular breast cancer, papillary breast cancer, Paget's disease(including juvenile Paget's disease) and inflammatory breast cancer;adrenal cancer such as but not limited to pheochromocytom andadrenocortical carcinoma; thyroid cancer such as but not limited topapillary or follicular thyroid cancer, medullary thyroid cancer andanaplastic thyroid cancer; pancreatic cancer such as but not limited to,insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secretingtumor, and carcinoid or islet cell tumor; pituitary cancers such as butlimited to Cushing's disease, prolactin-secreting tumor, acromegaly, anddiabetes insipius; eye cancers such as but not limited to ocularmelanoma such as iris melanoma, choroidal melanoma, and cilliary bodymelanoma, and retinoblastoma; vaginal cancers such as squamous cellcarcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamouscell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma,and Paget's disease; cervical cancers such as but not limited to,squamous cell carcinoma, and adenocarcinoma; uterine cancers such as butnot limited to endometrial carcinoma and uterine sarcoma; ovariancancers such as but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; cervicalcarcinoma; esophageal cancers such as but not limited to, squamouscancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoidcarcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma,verrucous carcinoma, and oat cell (small cell) carcinoma; stomachcancers such as but not limited to, adenocarcinoma, fungating(polypoid), ulcerating, superficial spreading, diffusely spreading,malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; coloncancers; colorectal cancer, KRAS mutated colorectal cancer; coloncarcinoma; rectal cancers; liver cancers such as but not limited tohepatocellular carcinoma and hepatoblastoma, gallbladder cancers such asadenocarcinoma; cholangiocarcinomas such as but not limited topapillary, nodular, and diffuse; lung cancers such as KRAS-mutatednon-small cell lung cancer, non-small cell lung cancer, squamous cellcarcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinomaand small-cell lung cancer; lung carcinoma; testicular cancers such asbut not limited to germinal tumor, seminoma, anaplastic, classic(typical), spermatocytic, nonseminoma, embryonal carcinoma, teratomacarcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such asbut not limited to, androgen-independent prostate cancer,androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, andrhabdomyosarcoma; penal cancers; oral cancers such as but not limited tosquamous cell carcinoma; basal cancers; salivary gland cancers such asbut not limited to adenocarcinoma, mucoepidermoid carcinoma, andadenoidcystic carcinoma; pharynx cancers such as but not limited tosquamous cell cancer, and verrucous; skin cancers such as but notlimited to, basal cell carcinoma, squamous cell carcinoma and melanoma,superficial spreading melanoma, nodular melanoma, lentigo malignantmelanoma, acrallentiginous melanoma; kidney cancers such as but notlimited to renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, transitional cell cancer (renal pelvis and/or ureter);renal carcinoma; Wilms' tumor; bladder cancers such as but not limitedto transitional cell carcinoma, squamous cell cancer, adenocarcinoma,carcinosarcoma. In addition, cancers include myxosarcoma, osteogenicsarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma,synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,bronchogenic carcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma and papillary adenocarcinomas.

In one aspect, the disclosure provides a method of treating cancer in asubject, comprising administering to the subject in need thereof aneffective amount of a compound described herein, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition ofdescribed herein. In some embodiments, the cancer can comprise cancercells with elevated levels of RAD 18 mRNA expression. In someembodiments, elevated levels of RAD 18 are elevated levels of RAD 18protein. In some embodiments, RAD 18 levels can be detected usingquantitative methods like microarray, RNA-Seq, or reverse transcriptasepolymerase chain reaction (RT-PCR). In some embodiments, the levels ofRAD 18 in a cancer cell can be detected prior to administration of thecompounds described herein. In some embodiments, RAD 18 levels can bedetected in a cancer sample obtained from a subject. In someembodiments, if a subject has elevated levels of RAD 18, the subject canbe treated with the compounds described herein. In some embodiments,elevated levels of RAD 18 in cancer cells indicate that a subjectadministered the compounds or pharmaceutical compositions describedherein is responsive to treatment using the compounds or pharmaceuticalcompositions described herein. In some embodiments, the compoundsdescribed herein are not administered to a subject with elevated levelsof RAD 18.

In some embodiments, the cancer is a DNA damage repair pathway deficientcancer. In some embodiments, the cancer is a PARP inhibitor resistant orrefractory BRCA1 or BRCA2-mutant cancer. In some embodiments, the cancercomprises cells with elevated levels of RAD 18, where the elevatedlevels of RAD 18 are at least as high as the RAD 18 mRNA and/or proteinlevels in ES2 cells or HEP3B217 cells.

In some embodiments, the cancer is a BRCA1 mutant cancer and/or a BRCA2mutant cancer. In some embodiments, the cancer is a BRCA1 or BRCA2wildtype cancer. In some embodiments, the cancer is a BRCA1-deficientcancer. In some embodiments, the cancer is a BRCA2-deficient cancer. Insome embodiments, the cancer that comprises cancer cells with a mutationin a gene that encodes BRCA1 and/or BRCA2. In some embodiments, thecancer is a BRCA1 mutant cancer and BRCA2 deficient cancer. In someembodiments, the cancer is a BRCA1 deficient cancer and BRCA2 mutantcancer. In some embodiments, the cancer comprises cells with elevatedlevels of RAD 18, where the elevated levels of RAD 18 are at least ashigh as the RAD 18 mRNA and/or protein levels in ES2 cells or HEP3B217cells.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed disclosure. The following examples further illustrate thedisclosure but, of course, should not be construed as in any waylimiting its scope.

The following synthetic schemes are provided for purposes ofillustration, not limitation. The following examples illustrate thevarious methods of making compounds described herein. It is understoodthat one skilled in the art may be able to make these compounds bysimilar methods or by combining other methods known to one skilled inthe art. It is also understood that one skilled in the art would be ableto make, in a similar manner as described below by using the appropriatestarting materials and modifying the synthetic route as needed. Ingeneral, starting materials and reagents can be obtained from commercialvendors or synthesized according to sources known to those skilled inthe art or prepared as described herein.

The compounds and salts of Formulas (IVa), (IVa-1), (IVa-2), and (VI)can be synthesized according to one or more illustrative schemes hereinand/or techniques known in the art. Materials used herein are eithercommercially available or prepared by synthetic methods generally knownin the art. These schemes are not limited to the compounds listed in theexamples or by any particular substituents, which are employed forillustrative purposes. Although various steps are described and depictedin the synthesis schemes below, the steps in some cases can be performedin a different order than the order shown below. Numberings or R groupsin each scheme do not necessarily correspond to that of the claims orother schemes or tables herein.

Examples A_Biological Assays Example A1: Enzymatic Assay

Human recombinant USP1/UAF1 expressed in baculovirus infected Sf21 cellswere used (R&D, E-568-050). Test compound and/or vehicle was incubatedwith 2 nM of USP1/UAF1 in modified HEPES buffer pH 8.0 for 15 minutes atRT. The reaction was initiated by addition of 500 nM of UbiquitinRhodamine 110 (R&D, U-555-050) for kinetic reading. Slope change offluorescence intensity was read spectrofluorimetrically at 485 nm/535nm. Dose response of test compounds or reference compound ML-323 wasanalyzed by nonlinear regression of GraphPad prism software. Results ofthe assay are illustrated in Table 2.

Example A2: MDA-MB-436 Breast Cancer Cell Culture

MDA-MB-436 cells were grown in Leibovitz's L-15 medium with 10 ug/mlinsulin, 16 ug/ml glutathione, 10% FBS. Cells were passaged atsubconfluence after trypsinization and maintained in incubators at 37°C. in a humidified atmosphere with 5% CO₂.

Example A3: MDA-MB-436 Breast Cancer Cell Proliferation Assay

Cell proliferation was determined using CellTiter-Glo® Luminescent CellViability Assay (Promega, #G7573). MDA-MB-436 cells were seeded in384-well plates and allowed to attach for 24 h. Compounds were addedinto 384-well plate by ECHO, and incubated at 37° C. in a humidifiedatmosphere with 5% CO₂. After 7 days, CellTiter-Glo was added into 384well plates, contents were mixed on an orbital shaker at 400 g for 2 minbefore centrifuging the plate for 2 min at 1000 rpm. After incubation atRT for 30 min, luminescence was read on envision. Results of the assayare illustrated in Table 2.

Examples B_Chemical Synthesis Example B1: LCMS Method

The LCMS methods used in the following synthesis procedures are providedin Table 3.

TABLE 3 LCMS Method codes (Flow expressed in mL/min; column temperature(T) in ° C.; Run time in minutes). Flow Method Mobile — code InstrumentColumn phase Gradient Column T Run time Method A Shimadzu: SunFire A FA0.1% 70% A for 0.4 2.0 mL/min 2.6 min LC-MS2020- C18 5 μm in water, min,to 5% A in — SPD-M20A 50*4.6 mm B: FA 0.1% 1.6 min, 5% A for 40° C. andAlltech in CH₃CN 0.6 min 3300ELSD Method B Shimadzu: SunFire A FA 0.1%50% A for 0.4 2.0 mL/min 2.6 min LC-MS2020- C18 5 μm in water, min, to5% A in — SPD-M20A 50*4.6 mm B: FA 0.1% 1.6 min, 5% A for 40° C. andAlltech in CH₃CN 0.6 min 3300ELSD

Example B2: Synthesis of Intermediate A

4-cyclopropyl-6-methoxypyrimidine

To a solution of 4-chloro-6-methoxypyrimidine (150.00 g, 1.04 mol) indioxane (1500 mL) and H₂O (300 mL) were added cyclopropylboronic acid(178.27 g, 2.08 mol), K₂CO₃ (286.82 g, 2.08 mol) and Pd(dppf)Cl₂ (75.92g, 0.10 mol). The reaction was stirred at 100° C. for 16 h under Aratmosphere. The mixture was diluted with water (500 mL) and extractedwith EtOAc (400 mL×3). The combined organic layers were washed withbrine (500 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography on silica gel eluted withPE/EtOAc=20/1 to afford desired product (82.10 g, 0.55 mol, 53%) as ayellow oil.

LCMS: Retention time: 1.157 min, (M+H)⁺=151.1, method A.

5-bromo-4-cyclopropyl-6-methoxypyrimidine

To a solution of 4-cyclopropyl-6-methoxypyrimidine (82.00 g, 546.01mmol) in EtOH (900 mL) was added Br₂ (30.85 mL, 600.61 mmol) at 0° C.The reaction mixture was stirred at room temperature for 16 h. Thesuspension was filtered and washed with MeOH (200 mL). The solid wasdried to afford desired product (99.70 g, 435.22 mmol, 79.7%) as a whitesolid.

LCMS: Retention time: 1.707 min, (M+H)⁺=229.1, method A.

4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

To a solution of 5-bromo-4-cyclopropyl-6-methoxypyrimidine (50.00 g,218.26 mmol) in DMSO (500 mL) were added4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(110.88 g, 436.53 mmol), KOAc (64.26 g, 654.79 mmol) and Pd(dppf)Cl₂(15.97 g, 21.83 mmol). The reaction was stirred at 100° C. for 16 hunder Ar atmosphere. The mixture was diluted with 600 mL of water andextracted with EtOAc (500 mL×3). The combined organic layers were washedwith brine (200 mL×3), dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by column chromatography onsilica gel eluted with PE/EtOAc=10:1 to afford desired product (28.00 g,101.40 mmol, 46%) as a white solid.

LCMS: Retention time: 1.627 min, (M+H)⁺=277.2, method A.

¹H NMR (400 MHz, DMSO-d₆): δ=8.59 (s, 1H), 3.86 (s, 3H), 2.05-2.02 (m,1H), 1.32 (s, 12H), 1.04-1.00 (m, 4H).

Example B3: Synthesis of Intermediate B

2-isopropylpyridin-3-yl trifluoromethanesulfonate

To a solution of 2-isopropylpyridin-3-ol (4.50 g, 32.80 mmol) inpyridine (20 mL) was added trifluoromethanesulfonic anhydride (5.44 mL,32.80 mmol) at 0° C. The mixture was stirred rt for 2 h. The mixture wasquenched with ice-water (30 mL) and basified with sat. NaHCO₃ solutiontill pH=7. The mixture was extracted with DCM (20 mL×3). The combinedorganic fractions were washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluting with PE/EtOAcfrom 50/1 to 20/1) to give desired product (7.88 g, 29.30 mmol, 89.3%)as a pale yellow oil. LCMS confirmed.

LCMS: Retention time: 1.597 min, (M+H)⁺=270.0, method A.

2-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 2-isopropylpyridin-3-yl trifluoromethanesulfonate (5.88 g,21.84 mmol), B₂pin₂ (11.09 g, 43.66 mmol), potassium acetate (4.28 g,43.66 mmol) and Pd(dppf)Cl₂ (1.60 g, 2.18 mmol) in dioxane (50 mL) wasstirred at 95° C. for 5 h under Ar. The mixture was concentrated, andthe residue was purified by column chromatography on silica gel (elutingwith DCM/MeOH from 100/1 to 40/1) to give desired product (5.20 g, 21.04mmol, 96%) as a brown oil.

LCMS: Retention time: 0.360 min, (M+H)⁺=166.1 (MS of correspondingboronic acid), method A.

Example B4: Synthesis of Intermediate C

2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole

To a solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (17.5 g, 64.86mmol) in H₂O (30 mL) was added NaOAc (8.87 g, 108.10 mmol). The mixturewas stirred at 100° C. for 1 h and then cooled to room temperature. Amixture of 4-bromobenzaldehyde (7.05 g, 38.1 mmol), NH₄OH (27.75 mL,216.19 mmol) and MeOH (50 mL) was added. The resulting mixture wasstirred at room temperature for 16 h. Then the reaction mixture wasconcentrated under reduced pressure. The precipitate was collected byfiltration and washed with ethyl acetate/petroleum ether (1/5, 60 mL).The solids were collected and dried under vacuum to give desired product(6.00 g, 20.6 mmol, 54%) as a yellow solid.

LCMS: Retention time: 1.267 min, (M+H)⁺=290.9, method B.

2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

To a solution of 2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole(6.00 g, 20.61 mmol) in DMF (100 mL) was added NaH (1.65 g, 41.22 mmol,60% dispersion in mineral oil) at 0° C. After stirred at 0° C. for 0.5h, CH₃I (3.51 g, 24.73 mmol) was added. The mixture was stirred at rtfor 16 h. Then the mixture was diluted with water (80 mL) and extractedwith EtOAc (70 mL×3). The combined organic fractions were washed withbrine (80 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (eluting with PE/EtOAc from 100/1 to 20/1) to give desiredproduct (2.81 g, 9.21 mmol, 45%) as a yellow solid. NMR confirmed.

H NMR: (400 MHz, CDCl₃) δ=7.63-7.60 (m, 2H), 7.53-7.50 (m, 2H), 7.31 (d,J=0.8 Hz, 1H), 3.76 (s, 3H)

Example B5: Synthesis of Intermediate D

tert-butyl3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50.00 g,223.93 mmol) in DMF (800 mL) were added I₂ (113.67 g, 447.87 mmol) andKOH (50.26 g, 895.74 mmol) at 0° C. The resulting mixture was stirred at60° C. for 16 h. Then the reaction mixture was cooled to rt, quenchedwith aq. Na₂SO₃ (100 mL) and water (1500 mL) and then extracted withEtOAc (350 mL×6). The combined organic layer was washed with brine (300mL×5), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was recrystallized from Et₂O (200 mL) to givedesired product (32.50 g, 93.07 mmol, 42%) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ=12.98 (s, 1H), 4.11 (s, 2H), 3.58 (t, J=5.6Hz, 2H), 2.63 (s, 2H), 1.42 (s, 9H)

tert-butyl3-iodo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (625mg, 1.79 mmol) in DMF (10 mL) were added Cs₂CO₃ (1750 mg, 5.37 mmol) andCH₃I (0.17 mL, 2.68 mmol) at room temperature. The reaction mixture wasstirred at rt for 16 h. The mixture was diluted with water (20 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (10 mL×3), dried over Na₂SO₄, filtered and concentrated undervacuum to afford desired product (630 mg, 1.73 mmol, crude yield 97%) asa yellow oil.

LCMS: Retention time: 1.825 min, (M+H)⁺=364.1, method A.

Separation of two N-methylation isomers by column chromatography onsilica gel eluted with ethyl acetate (from 0% to 10%) in petroleum ethergave pure product (350 mg, 0.96 mmol, 54%). 1H NMR (400 MHz, DMSO-d₆)δ=4.10 (s, 2H), 3.69 (s, 3H), 3.59 (t, J=5.8 Hz, 2H), 2.64 (t, J=5.6 Hz,2H), 1.42 (s, 9H).

tert-butyl3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl3-iodo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(200 mg, 0.55 mmol) in dioxane (5 mL) and H₂O (1 mL) were added4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(152 mg, 0.55 mmol), Pd(dppf)Cl₂ (40 mg, 0.06 mmol) and Na₂CO₃ (117 mg,1.10 mmol). The mixture was stirred at 100° C. for 6 h. The mixture wascooled to rt, diluted with water (15 mL) and extracted with EtOAc (15mL×3). The combined organic phases were washed with brine (15 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The residue waspurified by column chromatography on silica gel (eluting with PE/EtOAcfrom 100/0 to 5/1) to afford desired product (50 mg, 0.13 mmol, 24%) asa white solid.

LCMS: Retention time: 1.667 min, (M+H)⁺=386.3, method A.

¹H NMR (400 MHz, CDCl₃) δ=8.59 (s, 1H), 4.27 (s, 2H), 3.96 (s, 3H), 3.82(s, 3H), 3.80-3.72 (m, 2H), 2.74 (t, J=5.6 Hz, 2H), 2.16-2.06 (m, 1H),1.46 (s, 9H), 1.23-1.16 (m, 2H), 0.99-0.92 (m, 2H).

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

The solution of tert-butyl3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(50 mg, 0.13 mmol) in TFA (5 mL) and DCM (15 mL) was stirred at rt for 2h. The mixture was concentrated and dissolved in MeOH (10 mL).Sat.aqueous NaHCO₃ (15 mL) was added till pH=8. The mixture wasconcentrated and purified by reverse column chromatography (H₂O/CH₃CNfrom 100/0 to 4:1) to afford desired product (20 mg, 0.07 mmol, 54%) asa white solid.

LCMS: Retention time: 0.380 min, (M+H)⁺=286.2, method A.

¹H NMR (400 MHz, CDCl₃) δ=10.01 (s, 1H), 8.58 (s, 1H), 4.03 (s, 2H),3.93 (s, 3H), 3.85 (s, 3H), 3.52 (t, J=6.0 Hz, 2H), 3.06 (t, J=5.8 Hz,2H), 2.19-2.11 (m, 1H), 1.21-1.13 (m, 2H), 1.00-0.91 (m, 2H).

Example B6: Synthesis of Compound 1

tert-butyl3-(2-isopropylpyridin-3-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl3-iodo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(600 mg, 1.65 mmol) in dioxane (2 mL) and H₂O (0.4 mL) were added2-(propan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (612mg, 2.48 mmol), Na₂CO₃ (70 mg, 0.66 mmol) and Pd(dppf)Cl₂ (16 mg, 0.02mmol). The reaction mixture was stirred at 100° C. for 4 h undernitrogen atmosphere. The mixture was cooled to rt, quenched with 60 mLof water and extracted with EtOAc (60 mL×2). The combined organic layerswere washed with brine (50 mL×2), dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel eluted with PE/EtOAc=3/2 to afford desiredproduct (350 mg, 0.98 mmol, 59%) as a yellow solid.

LCMS: Retention time: 1.220 min, (M+H)⁺=357.2, method A.

3-(2-isopropylpyridin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of tert-butyl3-(2-isopropylpyridin-3-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(40 mg, 0.112 mmol) in methanol (5 mL) was added methanol hydrochloricacid (0.21 mL, 3M) slowly. The mixture was stirred at room temperaturefor 16 h. The pH value of reaction mixture was adjusted to 8-9 withNaHCO₃. The resulting suspension was filtered, and the filtrate wasconcentrated to give the crude product. The crude product was purifiedby C18 column chromatography (H₂O/CH₃CN from 100/1 to 30/70) to affordthe desired product (25 mg, 0.098 mmol, 87%) as a colorless oil.

LCMS: Retention time: 0.267 min, (M+H)⁺=257.1, method A.

3-(2-isopropylpyridin-3-yl)-1-methyl-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a mixture of3-(2-isopropylpyridin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(30 mg, 0.12 mmol),2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (36 mg, 0.12mmol) and t-BuONa (23 mg, 0.23 mmol) in toluene (10 mL) was addedPEPPSI-IPr (2.8 mg, 0.003 mmol). The mixture was stirred at 100° C. for16 h under N₂ atmosphere and then cooled to room temperature. Themixture was diluted with water (20 mL) and extracted with EtOAc (30mL×3). The organic layer was dried with Na₂SO₄, filtered andconcentrated to give a crude product. The crude product was purified byprep-TLC (PE/EtOAc=3/2) to afford desired product (4.80 mg, 0.01 mmol,8%).

LCMS: Retention time: 1.157 min, (M+H)⁺=481.2, method A.

¹H NMR: (400 MHz, DMSO-d₆) δ=8.57 (dd, J=4.8 Hz, J=1.6 Hz, 1H), 7.84 (s,1H), 7.64 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.29(dd, J=7.6 Hz, J=4.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 4.21 (s, 2H),3.79-3.77 (m, 5H), 3.74 (s, 3H), 3.46-3.42 (m, 1H), 2.88 (t, J 5.2 Hz,2H), 1.17 (d, J 6.8 Hz, 6H).

Example B7: Synthesis of Compound 2

5-bromo-4-isopropylpyrimidine

To a mixture of 5-bromopyrimidine (5.00 g, 31.45 mmol), isobutyric acid(3.325 g, 37.74 mmol), silver nitrate (2.67 g, 15.72 mmol) and potassiumpersulfate (10.2 g, 37.74 mmol) was added DCM (50 mL) and water (50 mL)at 0° C. The mixture was stirred at rt for 18 h. The solvent wasevaporated. The residue was diluted with EtOAc (60 mL), washed withbrine (60 mL), and dried over anhydrous Na₂SO₄. Evaporation of thesolvent followed by purification on silica gel column chromatography(eluting with PE/EtOAc from 1/0 to 80/1) gave desired product (1.30 g,6.47 mmol, 21% yield) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.71 (s, 1H), 3.50-3.46 (m, 1H),1.30-1.27 (m, 6H)

4-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

A mixture of 5-bromo-4-isopropylpyrimidine (350 mg, 1.74 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(442 mg, 1.74 mmol), Pd(dppf)Cl₂ (127 mg, 0.17 mmol) and KOAc (171 mg,1.74 mmol) in toluene (2.25 mL)/DME (1.5 mL)/EtOH (1.5 mL)/H₂O (0.75 mL)was heated at 90° C. using microwave under Ar for 0.5 h. The mixture wasused without work up in the next step.

LCMS: Retention time: 1.497 min, (M+H)⁺=249.2, method B.

tert-butyl3-(4-isopropylpyrimidin-5-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

A mixture of4-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(120 mg, 0.48 mmol), tert-butyl3-iodo-1-methyl-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate(176 mg, 0.48 mmol), Pd(dppf)Cl₂ (35 mg, 0.05 mmol) and Na₂CO₃ (103 mg,0.97 mmol) in dioxane (5 mL) and H₂O (1 mL) was heated and stirred at80° C. using microwave under Ar for 1 h. The mixture was diluted withwater (10 mL) and extracted with EtOAc (10 mL×3). The combined organicphases were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (PE/EtOAc=5/1) to give desired product (68 mg, 0.19 mmol, 39%)as a yellow oil.

LCMS: Retention time: 1.207 min, (M+H)⁺=358.2, method B.

3-(4-isopropylpyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A solution of tert-butyl3-(4-isopropylpyrimidin-5-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(96 mg, 0.27 mmol) in TFA (1 mL) and DCM (2 mL) was stirred at rt for 2h. The pH of mixture was adjusted to 8.0 with 8 N NH₃/MeOH andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM/MeOH=10/1) to give desired product (60 mg, 0.23 mmol,86.82%) as a white solid.

LCMS: Retention time: 0.607 min, (M+H)⁺=258.2, method A.

3-(4-isopropylpyrimidin-5-yl)-1-methyl-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A mixture of3-(4-isopropylpyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(50 mg, 0.19 mmol),2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (89 mg, 0.29mmol), Pd₂(dba)₃ (36 mg, 0.04 mmol), t-Bu XPhos (17 mg, 0.04 mmol) andSodium tert-butoxide (56 mg, 0.58 mmol) in dioxane (1.5 mL) was stirredat 100° C. under Ar for 16 h. The mixture was diluted with water (10 mL)and extracted with EtOAc (10 mL×3). The combined organic phases werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by prep-TLC(PE/EtOAc=1/1) to give desired product (1.30 mg, 0.0027 mmol, 1.4%).

LCMS: Retention time: 1.455 min, (M+H)⁺=482.3, method B.

¹H NMR (400 MHz, DMSO-d₆) δ=9.14 (s, 1H), 8.64 (s, 1H), 7.83 (s, 1H),7.52 (d, J=8.8 Hz, 2H), 7.09 (d, J=9.2 Hz, 2H), 4.29 (s, 2H), 3.78-3.73(m, 8H), 3.50-3.43 (m, 1H), 2.89 (t, J=4.8 Hz, 2H), 1.20-1.18 (m, 6H).

Example B8: Synthesis of Compound 3

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(130 mg, 0.46 mmol) in dioxane (5 mL) were added2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (167 mg,0.55 mmol), RuPhos Pd G3 (4 mg, 0.01 mmol), t-BuONa (61 mg, 0.64 mmol)and RuPhos (64 mg, 0.14 mmol). The mixture was stirred at 100° C. for 16h. Then the mixture was cooled to rt, diluted with water (15 mL) andextracted with EtOAc (15 mL×3). The combined organic phases were washedwith brine (15 mL) and dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by prep-TLC (PE/EtOAc=1/3) to afford desiredproduct (30.00 mg, 0.06 mmol, 13%).

LCMS: Retention time: 1.670 min, (M+H)⁺=510.3, method A.

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.83 (d, J=1.2 Hz, 1H), 7.52(d, J=8.8 Hz, 2H), 7.08 (d, J=9.2 Hz, 2H), 4.14 (s, 2H), 3.91 (s, 3H),3.80-3.70 (m, 8H), 2.85 (t, J=4.8 Hz, 2H), 2.16-2.12 (m, 1H), 1.04-1.03(m, 2H), 0.93-0.90 (m, 2H).

Example B9: Synthesis of Compound 4

2-(4-bromophenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

A mixture of 2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole (7.20 g,24.74 mmol) in DMF (20 mL) was added Cs₂CO₃ (20.15 g, 61.84 mmol) and2-iodopropane (8.41 g, 49.47 mmol). The mixture was stirred at 60° C.for 16 h. Then the mixture was diluted with water (100 mL) and extractedwith EtOAc (150 mL×3). The combined organic fractions were washed withbrine (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (eluting with PE/EtOAc from 10/1 to 6/1) to give desiredproduct (5.80 g, 17.41 mmol, 70.37%) as a yellow solid.

LCMS: Retention time: 1.600 min, (M+H)⁺=333.0, method B.

tert-butyl3-iodo-1-(methyl-d3)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.10g, 8.88 mmol) in DMF (35 mL) was added Cs₂CO₃ (4.34 g, 13.32 mmol) andCD₃I (1.93 g, 13.32 mmol). The mixture was stirred at rt for 16 h. Thenthe mixture was diluted with water (100 mL) and extracted with EtOAc (80mL×3). The combined organic fractions were washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (elutingwith PE/EA from 100/1 to 5/1) to give desired product (1.80 g, 4.92mmol, 55.4%) as a white solid.

LCMS: Retention time: 1.740 min, (M+H)+=367.1, method A.

tert-butyl3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d3)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of tert-butyl3-iodo-1-(methyl-d3)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(1.50 g, 4.10 mmol),4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(1.24 g, 4.49 mmol) and Na₂CO₃ (1.30 g, 12.29 mmol) in dioxane (10 mL)and H₂O (2 mL) was added Pd(dppf)Cl₂ (0.30 g, 0.41 mmol) under N₂. Themixture was stirred at 100° C. for 6 h and then cooled to roomtemperature. The mixture was diluted with water (60 mL) and extractedwith EtOAc (50 mL×3). The organic layers were collected, washed withbrine (60 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the crude product. The residue was purified bycolumn chromatography on silica gel (eluting with PE/EA from 100/1 to3/1) to give desired product (400 mg, 1.03 mmol, 25.12%) as a colorlessoil.

LCMS: Retention time: 1.630 min, (M+H)⁺=389.2, method A.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d3)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of tert-butyl3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d3)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (380 mg, 0.98 mmol) in DCM (10 mL) wasadded TFA (0.73 mL, 9.79 mmol). The mixture was stirred at roomtemperature for 2 h. NaHCO₃ powder was added to adjust pH to 7-8 andfiltered. The filtrate was concentrated under reduced pressure andpurified by column chromatography on silica gel (eluting with DCM/MeOHfrom 40/1 to 10/1) to give desired product (190 mg, 0.66 mmol, 67%) as ayellow solid

LCMS: Retention time: 0.517 min, (M+H)⁺=289.2, method A.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-1-(methyl-d3)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a mixture of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d3)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(170 mg, 0.59 mmol),2-(4-bromophenyl)-1-(propan-2-yl)-4-(trifluoromethyl)-1H-imidazole (197mg, 0.59 mmol), t-BuONa (454 mg, 4.72 mmol) and X-Phos (563 mg, 1.18mmol) in toluene (5 mL) was added Pd(OAc)₂ (13 mg, 0.06 mmol). Themixture was stirred at 100° C. for 16 h. Then the mixture was dilutedwith water (20 mL) and extracted with EtOAc (20 mL×3). The combinedorganic fractions were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC (PE/EA=1/3) to give desired product (117.08 mg,0.22 mmol, 97.76% purity, 37.29%).

LCMS: Retention time: 1.800 min, (M+H)⁺=541.3, method A.

1HNMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.07 (s, 1H), 7.36 (d, J=9.2Hz, 2H), 7.09 (d, J=9.2 Hz, 2H), 4.48-4.44 (m, 1H), 4.14 (s, 2H), 3.91(s, 3H), 3.77 (t, J=5.6 Hz, 2H), 2.85 (t, J=5.6 Hz, 2H), 2.16-2.14 (m,1H), 1.39 (d, J=6.8 Hz, 6H), 1.05-1.02 (m, 2H), 0.94-0.89 (m, 2H).

Example B10: Synthesis of Compound 5

2-bromo-5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (7.258 g, 26.88mmol) and NaOAc (4.41 g, 53.76 mmol) in H₂O (50 mL) was stirred at 100°C. for 1 h and then cooled to room temperature. Then the mixture of6-bromonicotinaldehyde (5.00 g, 26.88 mmol) and NH₄OH (13.80 mL, 107.52mmol) in MeOH (50 mL) was added to the above mixture. The resultingmixture was stirred at room temperature for 16 h. The mixture wasconcentrated, diluted with water (100 mL), and extracted with ethylacetate (100 mL×3). The combined organic layers were washed with brine(200 mL), dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluted withPE/EA=10/1 to afford desired product (5.30 g, 18.16 mmol, 67.6%) as awhite solid.

LCMS: Retention time: 1.647 min, (M+H)⁺=291.9, method A.

2-bromo-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

To a solution of2-bromo-5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (5.50 g, 18.83mmol) in DMF (55 mL) was added NaH (0.90 g, 22.60 mmol, 60% dispersionin mineral oil) at 0° C. under Ar. After stirred for 30 minutes, CH₃I(1.172 mL, 18.83 mmol) was added. The mixture was stirred at rt for 16h. Then the reaction mixture was quenched with water (30 mL) at 0° C.and extracted with ethyl acetate (100 mL×3). The combined organic layerswere washed with brine (200 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give the crude product. The crude productwas purified by flash chromatography on silica gel eluted with PE/EA=5/1to afford the desired product (2.35 g, 7.66 mmol, 40.7%) as a whitesolid.

LCMS: Retention time: 1.667 min, (M+H)⁺=306.0, method A.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(70 mg, 0.25 mmol) and2-bromo-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (83mg, 0.27 mmol) in dry DMSO (2 mL) was added Cs₂CO₃ (160 mg, 0.49 mmol).The mixture was degassed with N₂ for three times and stirred at 140° C.for 2 hours under microwave conditions. Then the reaction mixture wascooled to rt and water (10 mL) was added. The resulting mixture wasextracted with ethyl acetate (10 mL×3). The combined organic layer waswashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by prep-TLC(PE/EA=1/1) to afford the desired product (20.00 mg, 0.039 mmol, 15.6%).

LCMS: Retention time: 1.727 min, (M+H)⁺=511.2, method A.

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.87(d, J=1.2 Hz, 1H), 7.84 (dd, J=8.8, 2.4 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H),4.46 (s, 2H), 4.03 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.74(s, 3H), 2.86 (t, J=6.0 Hz, 2H), 2.18-2.15 (m, 1H), 1.05-1.02 (m, 2H),0.95-0.91 (m, 2H).

Example B11: Synthesis of Compound 6

5-bromo-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (9.07 g, 33.60mmol) and NaOAc (5.51 g, 67.20 mmol) in H₂O (50 mL) was stirred at 100°C. for 1 h and then cooled to rt. A mixture of5-bromopyridine-2-carbaldehyde (5.00 g, 26.88 mmol) and NH₄OH (17.26 mL,134.40 mmol) in MeOH (50 mL) was added and the resulting mixture wasstirred at rt for 16 h. Then the mixture was concentrated under reducedpressure to remove methanol and extracted with ethyl acetate (50 mL) forthree times. The combined organic fractions were washed with brine (80mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (eluting with PE/EA from 10/1 to 3/1) to give desired product (5.73g, 19.62 mmol, 73.00%) as a yellow solid.

LCMS: Retention time: 1.737 min, (M+H)⁺=291.9, method A.

5-bromo-2-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

To a solution of5-bromo-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (6.00 g, 20.54mmol) in DMF (70 mL) was added NaH (1.64 g, 41.08 mmol, 60% in mineraloil) at 0° C. under Ar. After stirring for 30 minutes, to the mixturewas added iodomethane (1.53 mL, 24.65 mmol). The resulting mixture wasstirred at room temperature for 16 h. The mixture was diluted with water(100 mL) and extracted with ethyl acetate (70 mL) for three times. Thecombined organic fractions were washed with brine (90 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (eluting with PE/EAfrom 100/1 to 3/1) to give desired product (5.00 g, 16.33 mmol, 79.5%)as a yellow solid.

LCMS: Retention time: 1.877 min, (M+H)⁺=306.0, method A.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(150 mg, 0.53 mmol),5-bromo-2-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (226mg, 0.74 mmol), X-Phos (501 mg, 1.05 mmol) and t-BuONa (101 mg, 1.05mmol) in toluene (5 mL) was added Pd(OAc)₂ (12 mg, 0.05 mmol). Themixture was degassed with N₂ for three times and stirred at 100° C. for16 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. Then the residue was diluted withwater (10 mL) and extracted with ethyl acetate (15 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct. The crude product was purified by prep-TLC (PE/EA=1/1) to givedesired product (130 mg, 0.24 mmol, 96.30% purity, 45%).

LCMS: Retention time: 1.567 min, (M+H)⁺=511.2, method A.

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.41 (s, 1H), 7.87-7.85 (m,2H), 7.51 (dd, J=2.8 Hz, 8.8 Hz, 1H), 4.21 (s, 2H), 4.02 (s, 3H), 3.92(s, 3H), 3.83 (t, J=5.6 Hz, 2H), 3.75 (s, 3H), 2.87 (t, J=5.6 Hz, 2H),2.16-2.13 (m, 1H), 1.05-1.03 (m, 2H), 0.93-0.90 (m, 2H).

Example B12: Synthesis of Compound 7

2-(4-bromo-3-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole

A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (8.313 g, 30.79mmol) and NaOAc (5.05 g, 61.57 mmol) in H₂O (50 mL) was stirred at 100°C. for 1 h and then cooled to rt. A mixture of4-bromo-3-fluorobenzaldehyde (5.00 g, 24.63 mmol), MeOH (50 mL), andNH₄OH (15.81 mL, 123.15 mmol) was added, and the resulting mixture wasstirred at rt for 16 h. The mixture was diluted with water (100 mL) andextracted with EtOAc (80 mL×5). The combined organic fractions werewashed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (eluting with PE/EA from 100/1 to 15/1) to give desiredproduct (3.60 g, 11.65 mmol, 47%) as a yellow solid.

LCMS: Retention time: 1.827 min, (M+H)⁺=308.9, method A.

2-(4-bromo-3-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

To a solution of2-(4-bromo-3-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole (3.60 g,11.65 mmol) in DMF (40 mL) was added NaH (0.93 g, 23.30 mmol, 60%dispersion in mineral oil) at 0° C. After stirred for 30 minutes, CH₃I(0.87 mL, 13.98 mmol) was added to the mixture.

The mixture was stirred at rt for 16 h. The mixture was diluted withwater (100 mL) and extracted with EtOAc (60 mL×5). The combined organicfractions were washed with brine (80 mL×3), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography onsilica gel (eluting with PE/EA from 100/1 to 20/1) to give desiredproduct (2.19 g, 6.78 mmol, 58.2%) as a yellow solid.

LCMS: Retention time: 1.117 min, (M+H)⁺=323.1, method A.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A mixture of2-(4-bromo-3-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole(181 mg, 0.56 mmol),3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(80 mg, 0.28 mmol), t-BuONa (216 mg, 2.24 mmol), X-Phos (1069 mg, 2.24mmol) and Pd(OAc)₂ (6 mg, 0.03 mmol) in toluene (5 mL) was stirred at100° C. for 16 h. Then the mixture was cooled to rt, concentrated andwater (10 mL) was added. The mixture was extracted with EtOAc (10 mL×3).The combined organic fractions were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified byprep-TLC (PE/EA=1/3) to give desired product (17.60 mg, 0.033 mmol,11.8%).

LCMS: Retention time: 1.780 min, (M+H)⁺=528.2, method A.

1HNMR (400 MHz, DMSO-d₆) δ=8.61 (s, 1H), 7.90 (s, 1H), 7.50 (dd, J=14,2.0 Hz, 1H), 7.42 (dd, J=8.4, 2.0 Hz, 1H), 7.17 (t, J=8.8 Hz, 1H), 4.00(s, 2H), 3.90 (s, 3H), 3.77 (s, 6H), 3.56 (t, J=5.6 Hz, 2H), 2.86 (t,J=5.2 Hz, 2H), 2.19-2.15 (m, 1H), 1.05-1.01 (m, 2H), 0.95-0.90 (m, 2H).

Example B13: Synthesis of Compound 8

2-(4-bromo-2-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole

To a solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (6.65 g, 24.63mmol) in H₂O (60 mL) was added NaOAc (4.04 g, 49.26 mmol). The mixturewas stirred at 100° C. for 1 h and then cooled to rt. A mixture of4-bromo-2-fluorobenzaldehyde (5 g, 24.63 mmol) and NH₄OH (12.65 mL,98.52 mmol) in MeOH (100 mL) was added and the resulting mixture wasstirred at rt for 16 h. Then the mixture was concentrated to removemethanol and extracted with ethyl acetate (30 mL) for three times. Thecombined organic layer was washed with brine (80 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was recrystallizedfrom (PE/EA=20/1, 100 mL) to give desired product (4.05 g, 13.10 mmol,53% yield) as a yellow solid.

LCMS: Retention time: 1.611 min, (M+H)⁺=309.0, method A.

2-(4-bromo-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole

To a solution of2-(4-bromo-2-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole (2.00 g,6.47 mmol) in DMF (30 mL) was added NaH (0.52 g, 12.94 mmol, 60%dispersion in mineral oil) at 0° C. After stirring for 0.5 h, MeI (0.60mL, 9.71 mmol) was added. The resulting mixture was stirred at rt for 16h. Then the mixture was quenched with saturated ammonium chloridesolution (100 mL) and water (50 mL) at 0° C. The mixture was extractedwith ethyl acetate (100 mL) for three times. The combined organicfractions were washed with brine (250 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography onsilica gel (eluting with PE/EtOAc from 100/0 to 12/1) to give desiredproduct (1.75 g, 5.42 mmol, 84% yield) as a light-yellow solid.

LCMS: Retention time: 1.677 min, (M+H)⁺=323.0, method A.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100 mg, 0.35 mmol),2-(4-bromo-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole(226 mg, 0.70 mmol), X-Phos (334 mg, 0.70 mmol) and t-BuONa (334 mg,0.70 mmol) in toluene (5 mL) was added Pd(OAc)₂ (8 mg, 0.04 mmol). Themixture was degassed with N₂ for three times and stirred at 100° C. for16 h. The reaction mixture was cooled to rt and concentrated. Then theresidue was diluted with water (10 mL) and extracted with ethyl acetate(15 mL×3). The combined organic layer was washed with brine (20 mL),filtered and concentrated to give the crude product. The crude productwas purified by prep-TLC (PE/EA=1/1) to give desired product (47.00 mg,0.089 mmol, 25%).

LCMS: Retention time: 1.577 min, (M+H)⁺=528.2, method A.

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.91 (s, 1H), 7.35-7.31 (m,1H), 6.98-6.91 (m, 2H), 4.18 (s, 2H), 3.91 (s, 3H), 3.81 (t, J=5.4 Hz,2H), 3.75 (s, 3H), 3.56 (s, 3H), 2.85 (t, J=5.2 Hz, 2H), 2.16-2.14 (m,1H), 1.04-1.02 (m, 2H), 0.93-0.90 (m, 2H)

Example B14: Synthesis of Compound 9

tert-butyl1-(difluoromethyl)-3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of tert-butyl3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2800mg, 8.02 mmol) and Potassium fluoride (932 mg, 16.04 mmol) inAcetonitrile (50 mL) was added diethyl (bromodifluoromethyl)phosphonate(2141 mg, 8.02 mmol) at rt. The mixture was stirred at rt for 16 h. Thenthe mixture was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluting withPE/EtOAc=10/1) to give desired product (1.565 g, 3.92 mmol, 48.9%) as awhite solid.

LCMS: Retention time: 1.526 min, (M+H)⁺=400.2, method B.

tert-butyl3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

A mixture of tert-butyl1-(difluoromethyl)-3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(1100 mg, 2.76 mmol),4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(1141 mg, 4.13 mmol), Pd(dppf)Cl₂ (202 mg, 0.28 mmol) and K₂CO₃ (762 mg,5.51 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 100° C.under Ar for 16 h. Then the mixture was cooled to rt, diluted with water(15 mL) and extracted with EtOAc (15 mL×3). The combined organicfractions were washed with brine (15 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluting with PE/EtOAc=5/1) to givedesired product (700 mg, 1.66 mmol, 60.1%) as a white solid.

LCMS: Retention time: 1.595 min, (M+H)⁺=422.2, method B.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A solution of tert-butyl3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(700 mg, 1.66 mmol) in DCM (6 mL) was added TFA (3 mL) at rt. Themixture was stirred at rt for 3 h. Then the mixture was concentrated andredissolved in DCM (15 mL). The pH of the solution was adjusted to 8.0with 8 N NH₃/MeOH and concentrated under reduced pressure. The residuewas purified by prep-TLC (DCM/MeOH=20/1) to give desired product (500mg, 1.56 mmol, 94%) as a white solid.

LCMS: Retention time: 0.678 min, (M+H)⁺=322.1, method B.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A mixture of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(200 mg, 0.62 mmol),2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (190 mg,0.62 mmol), Pd(OAc)₂ (14 mg, 0.06 mmol), X-Phos (593 mg, 1.25 mmol) andsodium tert-butoxide (120 mg, 1.25 mmol) in toluene (5 mL) was stirredat 100° C. under Ar for 16 h. Then the mixture was cooled to rt, dilutedwith water (10 mL) and extracted with EtOAc (10 mL×3). The combinedorganic phases were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC (PE/EtOAc=1/1) to give desired product (80 mg,0.147 mmol, 23.7%).

LCMS: Retention time: 1.531 min, (M+H)⁺=546.2, method B.

¹H NMR (400 MHz, DMSO-d₆) δ=8.69 (s, 1H), 8.00-7.70 (m, 2H), 7.54 (d,J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 4.17 (s, 2H), 3.94 (s, 3H),3.82-3.79 (m, 2H), 3.74 (s, 3H), 3.05-3.02 (m, 2H), 2.03-1.99 (m, 1H),1.10-1.06 (m, 2H), 0.98-0.94 (m, 2H).

Example B15: Synthesis of Compound 10

2-fluoro-5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

To a solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (69.29 g,256.78 mmol) in H₂O (150 mL) was added NaOAc (32.79 g, 399.73 mmol) at0° C. The mixture was stirred at 0° C. for 10 minutes and then heated at100° C. for another 1 hour under Ar. After cooling to rt,6-fluoronicotinaldehyde (25.00 g, 199.84 mmol), NH₄OH (93.39 g, 799.36mmol, 30%) and MeOH (200 mL) were added. The mixture was stirred at rtfor 16 hr under Ar. Then the mixture was concentrated to remove MeOH.The resulting suspension was filtered. The solid was washed with water(100 mL) and Et₂O (100 mL), and dried to give the title compound (46.05g, 199.22 mmol, 100% yield) as a yellow solid

LC-MS(ESI+): m/z 232.1 (M+H)⁺.

2-fluoro-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

To a mixture of2-fluoro-5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (10.00 g,43.26 mmol) in DMF (200 mL) were added Cs₂CO₃ (35.24 g, 108.16 mmol) and2-iodopropane (36.77 g, 216.31 mmol). The reaction mixture was stirredat 60° C. for 16 hr under Ar. After cooling to rt, to the mixture wasadded water (300 mL). After extraction with EtOAc (300 mL×2), thecombined organic layers were washed with brine (300 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by column chromatography on silica geleluting with ethyl acetate (from 0% to 8.5%) in petroleum ether to givethe title compound (4.24 g, 15.52 mmol, 36% yield) as a yellow solid.

LC-MS(ESI+): m/z 274.1 (M+H)⁺.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100 mg, 0.35 mmol) in dry DMF (3 mL) were added2-fluoro-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine(143 mg, 0.52 mmol) and Et₃N (106 mg, 1.05 mmol) at rt. The reactionmixture was stirred at 100° C. for 16 hr. After cooling to rt, to themixture was added water (30 mL). After extraction with EtOAc (20 mL×2),the combined organic fractions were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by prep-TLC (PE/EtOAc=1/3) to give the titlecompound (10.52 mg, 0.02 mmol, 6% yield).

LC-MS(ESI+): m/z 539.3 (M+H)⁺.

¹HNMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H),7.74-7.64 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.46 (s, 2H), 4.45-4.36 (m,1H), 4.08-4.00 (m, 2H), 3.91 (s, 3H), 3.76 (s, 3H), 2.90-2.82 (m, 2H),2.22-2.13 (m, 1H), 1.39 (d, J=6.4 Hz, 6H), 1.10-1.01 (m, 2H), 0.97-0.90(m, 2H).

Example B16: Synthesis of Compound 11

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-1-(methyl-d3)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d₃)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(400 mg, 1.39 mmol) (see Example B9 for its synthesis) in DMF (10 mL)were added TEA (0.193 mL, 1.39 mmol) and2-fluoro-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine(568 mg, 2.08 mmol). The reaction mixture was stirred at 100° C. for 16hr. After cooling to rt, to the mixture was added water (15 mL). Afterextraction with EtOAc (15 mL×3), the combined organic phases were washedwith brine (15 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified with prep-TLC (DCM/MeOH=20/1) to give the titlecompound (46.95 mg, 0.087 mmol, 6% yield).

LC-MS(ESI+): m/z 542.3 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 8.12(s, 1H), 7.70 (dd, J=9.2, 2.8 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 4.50-4.36(m, 3H), 4.03 (t, J=4.8 Hz, 2H), 3.91 (s, 3H), 2.86 (t, J=5.6 Hz, 2H),2.23-2.14 (m, 1H), 1.39 (d, J=6.8 Hz, 6H), 1.09-1.00 (m, 2H), 0.97-0.88(m, 2H).

Example B17: Synthesis of Compound 133-(4-cyclopropyl-6-methylpyrimidin-5-yl)-1-methyl-5-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

In a similar fashion according to the procedure for Compound 5, Compound13 was synthesized by replacing 4-chloro-6-methoxypyrimidine with4-chloro-6-methylpyrimidine. The crude product was purified by prep-TLC(DCM/EtOAc=2/1) to afford the title compound (3.54 mg, 1% yield).

LC-MS(ESI+): m/z 495.3 (M+H)⁺.

¹H NMR (400 MHz, MeOD-d₄) δ=8.83 (s, 1H), 8.39 (d, J=2.0 Hz, 1H),7.84-7.81 (m, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H),4.65-4.41 (m, 2H), 4.22-4.04 (m, 2H), 3.87 (s, 3H), 3.78 (s, 3H), 2.97(t, J=5.6 Hz, 2H), 2.36 (s, 3H), 1.94-1.88 (m, 1H), 1.28-1.16 (m, 2H),1.13-0.95 (m, 2H).

Example B18: Synthesis of Compound 15

2-fluoro-5-hydrazineylpyridine

A suspension of 6-fluoropyridin-3-amine (5.00 g, 44.60 mmol) in water(50 mL) and conc. HCl (30 mL) was cooled to −20° C. Then a solution ofsodium nitrite (3.08 g, 44.64 mmol) in water (20 mL) was added dropwise.The resulting mixture was stirred at −20° C. for 45 minutes.Subsequently, a solution of SnCl₂ (8.46 g, 44.62 mmol) in conc. HCl (25mL) was added. The mixture was stirred at 0° C. for another 1 hr. The pHof the mixture was adjusted to 10 with 1N NaOH aqueous solution. Afterextraction with ethyl acetate (80 mL×3), the combined organic layerswere washed with brine (80 mL), dried over Na₂SO₄, filtered andconcentrated to give the title compound (7 g, crude), which was useddirectly in next step.

LC-MS (ESI+): m/z 128.2 (M+H)⁺.

2-fluoro-5-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine

To a solution of 2-fluoro-5-hydrazineylpyridine (7.00 g, 11.01 mmol, 20%purity) in HFIP (50 mL) were added TEA (2.30 mL, 16.62 mmol) and1,1,1-trifluoropentane-2,4-dione (0.85 g, 5.52 mmol) slowly at 0° C. Thereaction mixture was stirred at 0° C. for 2 hr. Then the mixture wasconcentrated and diluted with water (15 mL). After extraction with ethylacetate (15 mL×3), the combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel eluted with 10% ethyl acetate in petroleum ether to give the titlecompound (700 mg, 2.86 mmol, 52% yield) as a yellow solid.

LC-MS (ESI+): m/z 246.1 (M+H)⁺.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(5-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of2-fluoro-5-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (120mg, 0.49 mmol) and3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(70 mg, 0.245 mmol) in DMF (5 mL) was added TEA (0.10 mL, 0.72 mmol).The reaction mixture was stirred at 100° C. for 16 hr. After cooling tort, to the mixture was added water (20 mL). After extraction with EtOAc(20 mL×3), the combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue, which was purified by pre-TLC (PE/EA=2/1) to afford thetitle product (18.65 mg, 15% yield).

LC-MS (ESI+): m/z 511.2 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.25 (d, J=2.8 Hz, 1H), 7.71(dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.72 (s, 1H), 4.46(s, 2H), 4.03 (t, J=6.0 Hz, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 2.87 (t,J=5.2 Hz, 2H), 2.27 (s, 3H), 2.23-2.12 (m, 1H), 1.07-1.00 (m, 2H),0.98-0.89 (m, 2H).

Example B19: Synthesis of Compound 163-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-ethyl-5-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

In a similar fashion according to the procedure for Compound 5, Compound16 was synthesized by replacing iodomethane with iodoethane. The crudeproduct was purified by prep-TLC (PE/EA=1/3) to give the title compound(83.21 mg, 0.16 mmol, 32% yield).

LC-MS(ESI+): m/z 525.2 (M+H)⁺.

¹HNMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.87(s, 1H), 7.84 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 4.46(s, 2H), 4.14-4.00 (m, 4H), 3.92 (s, 3H), 3.74 (s, 3H), 2.88 (t, J=5.2Hz, 2H), 2.26-2.16 (m, 1H), 1.34 (t, J=7.2 Hz, 3H), 1.08-1.00 (m, 2H),0.97-0.87 (m, 2H).

Example B20: Synthesis of Compound 17

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d3)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a mixture of2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (254 mg,0.83 mmol),3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d₃)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(200 mg, 0.69 mmol) (see Example B9 for synthesis), t-BuONa (533 mg,5.55 mmol) and X-Phos (661.6 mg, 1.39 mmol) in toluene (5 mL) was addedPd(OAc)₂ (15.58 mg, 0.07 mmol). The reaction mixture was stirred at 100°C. for 16 hr. After cooling to rt, to the mixture was added water (30mL). After extraction with EtOAc (30 mL×2), the combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by prep-TLC (PE/EtOAc=1/3) to give the title compound (117.08mg, 0.23 mmol, 33% yield).

LC-MS(ESI+): m/z 513.2 (M+H)⁺.

¹HNMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.83 (s, 1H), 7.52 (d, J=8.8Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 4.14 (s, 2H), 3.91 (s, 3H), 3.77 (t,J=5.6 Hz, 2H), 3.73 (s, 3H), 2.85 (t, J=5.2 Hz, 2H), 2.19-2.09 (m, 1H),1.09-1.00 (m, 2H), 0.97-0.86 (m, 2H).

Example B21: Synthesis of Compound 18

2-fluoro-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

To a solution of2-fluoro-5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (5.00 g, 21.63mmol) in DMF (50 mL) were added Cs₂CO₃ (14.10 g, 43.28 mmol) andiodomethane (4.61 g, 32.48 mmol). The reaction mixture was stirred at rtfor 16 hr under Ar. To the mixture was added water (300 mL). Afterextraction with EtOAc (200 mL×2), the combined organic layers werewashed with brine (200 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue, which was purified by columnchromatography on silica gel eluting with ethyl acetate (from 0% to 11%)in petroleum ether to give the title compound (4.09 g, 16.68 mmol, 77%yield) as a white solid.

LC-MS(ESI+): m/z 246.1 (M+H)⁺.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d3)-5-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A mixture of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d₃)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(200 mg, 0.69 mmol) (see Example B9 for synthesis),2-fluoro-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (255mg, 1.04 mmol) and TEA (0.29 mL, 2.10 mmol) in DMF (5 mL) was stirred at100° C. for 16 hr. After cooling to rt, to the mixture was added water(20 mL). After extraction with EtOAc (20 mL×2), the combined organiclayers were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by prep-TLC (PE/EA=1/3) to give the title compound (91.92 mg,0.18 mmol, 26% yield).

LC-MS(ESI+): m/z 514.2 (M+H)⁺.

¹HNMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.41 (d, J=2.4 Hz, 1H),7.90-7.80 (m, 2H), 7.03 (d, J=9.2 Hz, 1H), 4.46 (s, 2H), 4.03 (t, J=5.6Hz, 2H), 3.91 (s, 3H), 3.74 (s, 3H), 2.86 (t, J=5.6 Hz, 2H), 2.24-2.11(m, 1H), 1.09-1.00 (m, 2H), 0.98-0.87 (m, 2H).

Example B22: Synthesis of Compound 20

3-iodo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of tert-butyl3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.00g, 2.86 mmol) in DCM (20 mL) was added TFA (2.13 mL, 28.58 mmol). Thereaction mixture was stirred at rt for 2 hr. Then the mixture wasconcentrated and dissolved in DCM (20 mL). NaHCO₃ powder was added toadjust pH to 7-8. The suspension was filtered. The filtrate wasconcentrated to give a residue. The residue was purified by columnchromatography on silica gel (eluting with 2.5% to 10% MeOH in DCM) togive the title compound (1.10 g, crude) as a brown oil, which was usedin next step directly.

LC-MS(ESI+): m/z 249.9 (M+H)⁺.

3-iodo-5-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of 3-iodo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(715 mg, crude, 1.86 mmol) in DMF (10 mL) were added2-fluoro-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine(658 mg, 2.41 mmol) and TEA (0.84 mL, 6.07 mmol). The reaction mixturewas stirred at 100° C. for 16 hr. After cooling to rt, to the mixturewas added water (30 mL). After extraction with EtOAc (200 mL×2), thecombined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by column chromatography on silica gel(eluting with 0˜70% EtOAc in PE) to give the title compound (270 mg,0.54 mmol, 29%) as a yellow solid.

LC-MS(ESI+): m/z 503.1 (M+H)⁺.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a mixture of3-iodo-5-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(230 mg, 0.46 mmol),4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(164 mg, 0.59 mmol) and K₂CO₃ (126 mg, 0.91 mmol) in dioxane (8 mL) andH₂O (0.8 mL) was added Pd(PPh₃)₄ (105 mg, 0.09 mmol). The reactionmixture was stirred at 100° C. for 16 hr. After cooling to rt, to themixture was added water (20 mL). After extraction with EtOAc (20 mL×3),the combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by prep-TLC (PE/EtOAc=1/3) to give the titlecompound (43.30 mg, 0.08 mmol, 17%).

LC-MS(ESI+): m/z 525.3 (M+H)⁺.

¹HNMR (400 MHz, CDCl₃) δ=8.63 (s, 1H), 8.30 (s, 1H), 7.73 (d, J=8.0 Hz,1H), 7.39 (s, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.56 (s, 2H), 4.55-4.48 (m,1H), 4.14-4.06 (m, 2H), 3.98 (s, 3H), 3.03-2.94 (m, 2H), 2.02-1.94 (m,1H), 1.45 (d, J=6.4 Hz, 6H), 1.28-1.20 (m, 2H), 1.04-0.96 (m, 2H).

Example B23: Synthesis of Compound 21

6-cyclopropyl-5-(5-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrimidin-4-ol

A solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(70 mg, 0.13 mmol) in HCl (6 mL, 3M in MeOH) was stirred at 100° C. for16 hr. After cooling to rt, the mixture was concentrated under reducedpressure to give a residue, which was purified by pre-HPLC (column:Waters X bridge C18 10 um OBD 19*250 mm; mobile phase: [0.1% NH₄HCO₃ inwater-MeCN]; B %: 30%-95%, 6.48 min)) to give the title compound (24.00mg, 0.05 mmol, 38% yield).

LC-MS(ESI+): m/z 525.2 (M+H)⁺.

¹HNMR (400 MHz, DMSO-d₆) δ=12.37 (br s, 1H), 8.25 (d, J=2.4 Hz, 1H),8.12 (s, 1H), 8.08 (s, 1H), 7.73-7.64 (m, 1H), 7.01 (d, J=8.8 Hz, 1H),4.46 (s, 2H), 4.45-4.35 (m, 1H), 4.01 (t, J=5.6 Hz, 2H), 3.73 (s, 3H),2.83 (t, J=5.6 Hz, 2H), 2.28-2.16 (m, 1H), 1.39 (d, J=6.8 Hz, 6H),1.03-0.94 (m, 2H), 0.89-0.82 (m, 2H).

Example B24: Synthesis of Compound 24

3-bromo-2-(difluoromethoxy)pyridine

3-bromopyridin-2-ol (10.00 g, 57.47 mmol) was dissolved in MeCN (100mL). Then 2,2-difluoro-2-(fluorosulfonyl) acetic acid (15.34 g, 86.14mmol) and sodium sulfate (8.97 g, 63.15 mmol) were added at 0° C. within20 minutes. The reaction mixture was warmed to rt and stirred at rt for16 hr. Then the mixture was filtered and concentrated. To the residuewas added water (50 mL). After extraction with ethyl acetate (70 mL×3),the combined organic layers were washed with saturated sodiumbicarbonate aqueous solution (30 mL), brine (80 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue,which was purified by column chromatography on silica gel eluted with 5%to 15% ethyl acetate in petroleum ether to give the title product (9.96g, 44.46 mmol, 77% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ=8.13 (dd, J=1.6 Hz, J=4.8 Hz, 1H), 7.94 (dd,J=1.6 Hz, J=7.6 Hz, 1H), 7.65-7.27 (m, 1H), 7.01 (dd, J=4.8 Hz, J=7.6Hz, 1H).

2-(difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 3-bromo-2-(difluoromethoxy)pyridine (100 mg, 0.45 mmol)in dioxane (10 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (168 mg,0.66 mmol), KOAc (131.5 mg, 1.34 mmol) and Pd(dppf)Cl₂ (32.67 mg, 0.04mmol). The reaction mixture was stirred at 100° C. for 16 hr. Aftercooling to rt, the mixture was concentrated under reduced pressure. Tothe residue was added water (10 mL). After extraction with ethyl acetate(10 mL×3), the combined organic layers were washed with brine (15 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue, which was purified by pre-TLC (PE/EA=3/1) to give thetitle compound (75 mg, 0.28 mmol, 62% yield) as a colorless oil.

LC-MS (ESI+): m/z 272.1 (M+H)⁺.

tert-butyl3-(2-(difluoromethoxy)pyridin-3-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of tert-butyl3-iodo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(500 mg, 1.38 mmol),2-(difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(560 mg, 2.07 mmol) and Na₂CO₃ (146 mg, 1.38 mmol) in dioxane/water (5mL/1 mL) was added Pd(dppf)Cl₂ (114 mg, 0.14 mmol). The reaction mixturewas stirred at 100° C. for 16 hr. After cooling to rt, the mixture wasconcentrated and diluted with water (20 mL). The resulting mixture wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (30 mL), dried over Na₂SO₄, filtered and concentratedto give a residue, which was purified by column chromatography on silicagel eluted with 5%˜ 20% ethyl acetate in petroleum ether to give thetitle compound (330 mg, 0.87 mmol, 63% yield) as a white solid.

LC-MS (ESI+): m/z 381.1 (M+H)⁺.

3-(2-(difluoromethoxy)pyridin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of tert-butyl3-(2-(difluoromethoxy)pyridin-3-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(330 mg, 0.87 mmol) in DCM (10 mL) was added TFA (989 mg, 8.67 mmol).The reaction mixture was stirred at rt for 2 hr. Then the mixture wasconcentrated and diluted with ethyl acetate (10 mL). The pH of theresulting mixture was adjusted to 8-9 with NaHCO₃ powder. Then themixture was filtered. The filtrate was concentrated to give a residue,which was purified by pre-TLC (DCM/MeOH=10/1) to give the title product(160 mg, 0.57 mmol, 66% yield) as white solid.

LC-MS (ESI+): m/z 281.2 (M+H)⁺.

3-(2-(difluoromethoxy)pyridin-3-yl)-1-methyl-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a mixture of3-(2-(difluoromethoxy)pyridin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(160 mg, 0.57 mmol),2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (348 mg,1.14 mmol), X-Phos (544 mg, 1.14 mmol) and sodium tert-butoxide (110 mg,1.14 mmol) in toluene (10 mL) was added Pd(OAc)₂ (12.82 mg, 0.06 mmol).The reaction mixture was stirred at 100° C. for 16 hr. After cooling tort, the mixture was concentrated and diluted with water (10 mL). Theresulting mixture was extracted with ethyl acetate (10 mL×3). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by pre-TLC (PE/EA=2/1) to give the titlecompound (106.00 mg, 0.21 mmol, 37% yield).

LC-MS (ESI+): m/z 505.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.29 (dd, J=2.0 Hz, J=4.8 Hz, 1H), 8.08-7.67(m, 3H), 7.51 (d, J=8.8 Hz, 2H), 7.35 (dd, J=4.8 Hz, J=7.2 Hz, 1H), 7.08(d, J=8.8 Hz, 2H), 4.35 (s, 2H), 3.81-3.74 (m, 5H), 3.73 (s, 3H), 2.85(t, J=5.6 Hz, 2H).

Example B25: Synthesis of Compound 25

5-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-fluoropyridine

To a solution of2-fluoro-5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine (3.00 g, 12.98mmol) in DMF (30 mL) was added NaH (0.78 g, 19.5 mmol, 60% dispersion inmineral oil) at 0° C. The mixture was stirred at 0° C. for 30 minutes.Then iodoethane (3.04 g, 19.49 mmol) was added to the mixture at 0° C.The mixture was stirred at rt for 16 hr. Then to the mixture was addedwater (100 mL). After extraction with EtOAc (100 mL×2), the combinedorganic layers were washed with brine (100 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue,which was purified by column chromatography on silica gel eluting withethyl acetate (from 0% to 11%) in petroleum ether to give the titlecompound (1.64 g, 6.33 mmol, 49% yield) as a yellow solid.

LC-MS(ESI+): m/z 260.1 (M+H)⁺.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(5-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A mixture of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(150 mg, 0.53 mmol),5-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-fluoropyridine (204mg, 0.79 mmol) and TEA (160 mg, 1.58 mmol) in DMF (5 mL) was stirred at100° C. for 16 hr. After cooling to rt, to the mixture was added water(20 mL). After extraction with EtOAc (20 mL×2), the combined organiclayers were washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by prep-TLC (PE/EA=1/3) to give the title compound (75.28 mg,0.14 mmol, 26% yield).

LC-MS(ESI+): m/z 525.2 (M+H)+.

¹HNMR (400 MHz, DMSO-d₆) δ=8.63 (d, J=4.0 Hz, 1H), 8.32 (d, J=2.4 Hz,1H), 7.97 (d, J=1.2 Hz, 1H), 7.77 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.03 (d,J=8.8 Hz, 1H), 4.46 (s, 2H), 4.12-3.98 (m, 4H), 3.91 (s, 3H), 3.76 (s,3H), 2.86 (t, J=5.2 Hz, 2H), 2.24-2.11 (m, 1H), 1.32 (t, J=7.6 Hz, 3H),1.09-1.00 (m, 2H), 0.98-0.87 (m, 2H).

Synthesis of Intermediate 26.1

5-bromopyrimidine-2-carbaldehyde

DIBAL-H (6.49 mL, 6.49 mmol, 1M in TIF) was added dropwise to a cooledsolution of ethyl 5-bromopyrimidine-2-carboxylate (1.00 g, 4.33 mmol) inTHE (10 mL) at −75° C. The reaction mixture was stirred at −75° C. for 1hr. Then the mixture was quenched by addition of saturated NH₄Cl aqueoussolution (20 mL) and EtOAc (20 mL). 2N HCl aqueous solution (4 mL) wasadded to clear the emulsion formed. The mixture was extracted with EtOAc(20 mL×3). The combined organic layers were washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a crude product (450 mg, 2.41 mmol, 56% yield), which was used innext step directly.

Example B26: Synthesis of Compound 263-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(2-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidin-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

In a similar fashion according to the procedure for Compound 6, Compound26 was synthesized by replacing 5-bromopicolinaldehyde with(intermediate 26.1) 5-bromopyrimidine-2-carbaldehyde. The crude productwas purified by prep-TLC (DCM/MeOH=20/1) to give the title compound(27.47 mg, 19% yield).

LC-MS(ESI+): m/z 512.3 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.67 (s, 2H), 8.63 (s, 1H), 7.93 (s, 1H),4.27 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.91-3.83 (m, 2H), 3.75 (s,3H), 2.94-2.86 (m, 2H), 2.18-2.04 (m, 1H), 1.08-1.00 (m, 2H), 0.96-0.85(m, 2H).

Example B27: Synthesis of Compound 27

2-chloro-5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidine

A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (3.60 g, 13.34mmol) and NaOAc (1094 mg, 13.34 mmol) in H₂O (5 mL) was stirred at 100°C. for 1 hr. After cooling to rt, a mixture of2-chloropyrimidine-5-carbaldehyde (950 mg, 6.66 mmol), MeOH (10 mL) andNH₄OH (10 mL) was added. The resulting mixture was stirred at rt for 16hr. Then to the mixture was added water (50 mL). After extraction withEtOAc (50 mL×3), the combined organic layers were washed with brine (70mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue, which was purified by column chromatography on silicagel eluting with ethyl acetate (from 0% to 20%) in petroleum ether togive the title compound (970 mg, 3.90 mmol, 59% yield).

LC-MS(ESI+): m/z 249.1 (M+H)⁺.

2-chloro-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidine

2-chloro-5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidine (950 mg,3.82 mmol) was dissolved in DMF (10 mL). Cs₂CO₃ (1867 mg, 5.73 mmol) wasadded. The mixture was cooled to 0° C. and stirred at 0° C. for 30 min.Then CH₃I (813 mg, 5.73 mmol) was added. The reaction mixture wasstirred at rt for 16 hr. Then to the mixture was added water (30 mL).After extraction with EtOAc (20 mL×3), the combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue, which was purified by columnchromatography on silica gel eluting with ethyl acetate (from 1% to 15%)in petroleum ether to give the title compound (480 mg, 1.83 mmol, 48%yield).

LC-MS(ESI+): m/z 263.1 (M+H)+.

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(245 mg, 0.86 mmol) and2-chloro-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidine(150 mg, 0.57 mmol) in i-PrOH (5 mL) was added DIPEA (0.28 mL, 1.61mmol). The reaction mixture was stirred at 100° C. for 16 hr. Aftercooling to rt, the mixture was concentrated. To the residue was addedwater (15 mL). After extraction with EtOAc (20 mL×3), the combinedorganic layers were washed with brine (40 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue,which was purified by prep-TLC (PE/EA=1/3) to give the title compound(122.65 mg, 0.24 mmol, 42% yield). LC-MS(ESI+): m/z 512.1 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.69 (s, 2H), 8.62 (s, 1H), 7.93 (s, 1H),4.66 (s, 2H), 4.20 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 3.76 (d, J=4.8 Hz,6H), 2.87 (t, J=4.8 Hz, 2H), 2.25-2.13 (m, 1H), 1.07-1.00 (m, 2H),0.98-0.90 (m, 2H).

Example B28: Synthesis of Compound 283-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

In a similar fashion according to the procedure for Compound 27,Compound 28 was synthesized by replacing2-chloropyrimidine-5-carbaldehyde with 5-chloropyrazine-2-carbaldehyde.In the last step, TEA in DMF was used.

The crude product was purified by prep-TLC (DCM/MeOH=20/1) to afford thetitle compound (12.14 mg, 8% yield).

LC-MS(ESI+): m/z 512.3 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.65 (s, 1H), 8.62 (s, 1H), 8.48 (s, 1H),7.92 (s, 1H), 4.53 (s, 2H), 4.08 (t, J=5.2 Hz, 2H), 3.95 (s, 3H), 3.91(s, 3H), 3.75 (s, 3H), 2.90 (t, J=4.8 Hz, 2H), 2.22-2.13 (m, 1H),1.09-1.00 (m, 2H), 0.97-0.87 (m, 2H).

Synthesis of Intermediate 29.1

6-chloropyridazine-3-carbaldehyde

DIBAL-H (5.36 mL, 5.36 mmol, 1M in THF) was added dropwise to a solutionof ethyl 6-chloropyridazine-3-carboxylate (500 mg, 2.68 mmol) in THF (10mL) at 0° C. under N₂. The mixture was stirred at 0° C. for 0.5 hr. Thenthe mixture was quenched with 20 mL of ice water, 1N HCl aqueoussolution (15 mL) and then neutralized with saturated sodium bicarbonateaqueous solution (15 mL) at 0° C. The resulting mixture was extractedwith dichloromethane (20 mL×3). The combined organic phases were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated to givethe title compound (350 mg, 2.46 mmol, 92% yield) as a brown oil, whichwas used in nest step directly.

¹H NMR (400 MHz, CDCl₃) δ 10.36 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.72(dd, J=8.8, 0.4 Hz, 1H).

Example B29: Synthesis of Compound 293-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-5-(6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridazin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

In a similar fashion according to the procedure for Compound 28,Compound 29 was synthesized by replacing 5-chloropyrazine-2-carbaldehydewith (intermediate 29.1) 6-chloropyridazine-3-carbaldehyde.

The crude product was purified by prep-TLC (DCM/MeOH=20:1) to give thetitle compound (13.15 mg, 9% yield).

LC-MS(ESI+): m/z 512.4 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 8.01-7.90 (m, 2H), 7.51 (d,J=10.0 Hz, 1H), 4.56 (s, 2H), 4.11 (t, J=5.6 Hz, 2H), 4.04 (s, 3H), 3.91(s, 3H), 3.76 (s, 3H), 2.91 (t, J=4.8 Hz, 2H), 2.24-2.12 (m, 1H),1.10-1.00 (m, 2H), 0.97-0.89 (m, 2H).

Example B30: Synthesis of Compound 30

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-1-(methyl-d₃)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a mixture of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(methyl-d₃)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(150 mg, 0.52 mmol) (see example B9 for synthesis),2-(4-bromo-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole(336 mg, 1.04 mmol) (see Example B13 for synthesis), t-BuONa (399.9 mg,4.16 mmol) and X-Phos (496 mg, 1.04 mmol) in toluene (6 mL) was addedPd(OAc)₂ (11.68 mg, 0.052 mmol). The reaction mixture was stirred at100° C. for 16 hr. After cooling to rt, to the mixture was added water(30 mL). After extraction with EtOAc (30 mL×2), the combined organiclayers were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by prep-TLC (PE/EA=1/3) to give the title compound (93.61 mg,0.18 mmol, 35% yield).

LC-MS(ESI+): m/z 531.2 (M+H)⁺.

¹HNMR (400 MHz, DMSO-d₆) δ=8.62 (s, 1H), 7.90 (s, 1H), 7.33 (t, J=8.8Hz, 1H), 7.01-6.88 (m, 2H), 4.18 (s, 2H), 3.91 (s, 3H), 3.81 (t, J=5.6Hz, 2H), 3.56 (s, 3H), 2.85 (t, J=5.6 Hz, 2H), 2.20-2.10 (m, 1H),1.08-1.00 (m, 2H), 0.96-0.86 (m, 2H).

Example B31: Synthesis of Compound 31

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-5-(5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100 mg, 0.31 mmol) (see Example B14 for synthesis) in DMF (3 mL) wereadded 2-fluoro-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine(114 mg, 0.46 mmol) and TEA (0.13 mL, 0.94 mmol) at rt. The reactionmixture was stirred at 100° C. for 48 hr under N₂ atmosphere. Aftercooling to rt, to the mixture was added water (15 mL). After extractionwith EtOAc (20 mL×3), the combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue, which was purified by prep-TLC(PE/EtOAc=1/1) to give the title compound (56.20 mg, 0.10 mmol, 32%yield).

LC-MS(ESI+): m/z 547.3 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.69 (s, 1H), 8.43 (d, J=2.4 Hz, 1H),8.03-7.68 (m, 3H), 7.08 (d, J=9.2 Hz, 1H), 4.50 (s, 2H), 4.07 (t, J=5.6Hz, 2H), 3.94 (s, 3H), 3.75 (s, 3H), 3.04 (t, J=5.2 Hz, 2H), 2.08-1.96(m, 1H), 1.12-1.04 (m, 2H), 1.01-0.93 (m, 2H).

Example B32: Synthesis of Compound 32

3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-5-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a solution of3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(difluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100 mg, 0.31 mmol) (see Example B14 for synthesis) in DMF (3 mL) wereadded2-fluoro-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine(128 mg, 0.47 mmol) and TEA (0.13 mL, 0.94 mmol) at rt. The reactionmixture was stirred at 100° C. for 48 hr under N₂ atmosphere. Aftercooling to rt, to the mixture was added water (20 mL). After extractionwith EtOAc (20 mL×3), the combined organic layers were washed with brine(25 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue, which was purified by prep-TLC(PE/EtOAc=1/1) to give the title compound (47.13 mg, 0.08 mmol, 26%yield).

LC-MS(ESI+): m/z 575.3 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ=8.69 (s, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.13(d, J=1.2 Hz, 1H), 8.03-7.68 (m, 2H), 7.08 (d, J=9.2 Hz, 1H), 4.50 (s,2H), 4.46-4.37 (m, 1H), 4.11-4.02 (m, 2H), 3.94 (s, 3H), 3.08-3.00 (m,2H), 2.08-1.98 (m, 1H), 1.39 (d, J=6.4 Hz, 6H), 1.12-1.03 (m, 2H),1.02-0.93 (m, 2H).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound having the structure of Formula(IVa-2), or a pharmaceutically acceptable salt thereof,

wherein Y¹ is N or CR^(Y1); Y² is N or CR^(Y2); Y³ is CR^(Y3); Y⁴ isCR^(Y4); each of R^(Y1), R^(Y2), R^(Y3), and R^(Y4) is independentlyhydrogen or C₁-C₆ alkyl; R¹ is hydrogen or C₁-C₆alkyl;

and each R^(A) is independently OH, C₁₋₆ alkoxyl, C₁₋₆ alkyl, C₁₋₆haloalkyl, or C₃-C₆ cycloalkyl; and R^(B1) is 5 membered heteroaryloptionally substituted with one or more substituents selected from C₁₋₃haloalkyl and C₁₋₃ alkyl.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: Y¹ is CH, Y² is CH,Y³ is CH, and Y⁴ is CH; Y¹ is CH, Y² is N, Y³ is CH, and Y⁴ is CH; or Y¹is N, Y² is CH, Y³ is CH, and Y⁴ is CH.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is —CH₃.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein


5. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(B1) is


6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 15. A method of treatinga disease or disorder associated with ubiquitin specific protease 1(USP1) comprising administering to a subject a compound of claim 6, or apharmaceutically acceptable salt thereof, wherein the subject has adisease or disorder associated with USP1.
 16. The method of claim 15,wherein the disease or disorder is a cancer, and wherein the cancer is aBRCA1 mutant cancer, a BRCA2 mutant cancer, or a BRCA1 and BRCA2 mutantcancer.
 17. The method of claim 15, wherein the disease or disorder is acancer, and wherein the cancer is a DNA damage repair pathway deficientcancer.
 18. The method of claim 15, wherein the disease or disorder is acancer, and wherein the cancer is a homologous recombination deficient(HRD) cancer.
 19. A pharmaceutical composition comprising (i) a compoundhaving the structure of Formula (IVa-2), or a pharmaceuticallyacceptable salt thereof,

wherein Y¹ is N or CR^(Y1); Y² is N or CR^(Y2); Y³ is CR^(Y3); Y⁴ isCR^(Y4); each of R^(Y1), R^(Y2), R^(Y3), and R^(Y4) is independentlyhydrogen or C₁-C₆ alkyl; R¹ is hydrogen or C₁-C₆alkyl;

and each R^(A) is independently OH, C₁₋₆ alkoxyl, C₁₋₆ alkyl, C₁₋₆haloalkyl, or C₃-C₆ cycloalkyl; and R^(B1) is 5 membered heteroaryloptionally substituted with one or more substituents selected from C₁₋₃haloalkyl and C₁₋₃ alkyl; and (ii) a pharmaceutically acceptableexcipient.
 20. The pharmaceutical composition of claim 19, wherein: Y¹is CH, Y² is CH, Y³ is CH, and Y⁴ is CH; Y¹ is CH, Y² is N, Y³ is CH,and Y⁴ is CH; or Y¹ is N, Y² is CH, Y³ is CH, and Y⁴ is CH.
 21. Thepharmaceutical composition of claim 19, wherein R¹ is —CH₃;

and R^(B1) is


22. The pharmaceutical composition of claim 19, wherein the compound isselected from:

or a pharmaceutically acceptable salt thereof.
 23. The pharmaceuticalcomposition of claim 19, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 24. The pharmaceuticalcomposition of claim 19, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 25. The pharmaceuticalcomposition of claim 19, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 26. The pharmaceuticalcomposition of claim 19, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 27. The pharmaceuticalcomposition of claim 19, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 28. The pharmaceuticalcomposition of claim 19, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 29. The pharmaceuticalcomposition of claim 19, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 30. The pharmaceuticalcomposition of claim 19, wherein the compound is

or a pharmaceutically acceptable salt thereof.